KRAS

Summary

KRAS (KRas proto-oncogene, GTPase, HGNC:6407) is a protein-coding gene on chromosome 12p12.1, encoding GTPase KRas (P01116). Signal transducer in the Ras-MAPK signaling pathway that regulates cell proliferation and survival. In precision oncology, KRAS G12C confers sensitivity to Sotorasib in Lung Non-small Cell Carcinoma (CIViC Level A); 246 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 52.4% of cell lines).

This gene, a Kirsten ras oncogene homolog from the mammalian ras gene family, encodes a protein that is a member of the small GTPase superfamily. A single amino acid substitution is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma. Alternative splicing leads to variants encoding two isoforms that differ in the C-terminal region.

Source: NCBI Gene 3845 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 581 total — 39 pathogenic, 46 likely-pathogenic (top 6% of genes corpus-wide)
• Regional missense constraint (gnomAD): 1 of 2 regions constrained (≈63% of expected missense variation)
• GTEx eGene: eQTL in 19 tissues, sQTL in 0 (q < 0.05)
• Phenotypes (HPO): 401
• Drug target: yes — 2 curated mechanism-of-action drugs, 1 via a complex or family; 11 molecules with ChEMBL bioactivity (top 3% of genes corpus-wide)
• Approved drugs (ChEMBL mechanism of action): 2 — Adagrasib, Sotorasib
• Precision-oncology evidence (CIViC): 247 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 36 cancer types (inferred from mutation patterns)
• Cancer dependency (DepMap): dependent in 52.4% of screened cell lines
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.26 (highly constrained)
• MANE Select transcript: NM_004985
• Interaction hub: 8,288 STRING partners (top 1% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6407
Approved symbol	KRAS
Name	KRas proto-oncogene, GTPase
Location	12p12.1
Locus type	gene with protein product
Status	Approved
Aliases	KRAS1, K-Ras4B
Ensembl gene	ENSG00000133703
Ensembl biotype	protein_coding
OMIM	190070
Entrez	3845

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 20 protein_coding, 9 nonsense_mediated_decay, 1 retained_intron

MANE Select: ENST00000311936 · MANE Plus Clinical: ENST00000256078

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 5: 1

ENST00000311936, ENST00000256078, ENST00000556131, ENST00000557334, ENST00000685328, ENST00000686877, ENST00000686969, ENST00000687356, ENST00000688228, ENST00000688940, ENST00000690406, ENST00000690804, ENST00000692768, ENST00000693229, ENST00000894155, ENST00000940422, ENST00000982952, ENST00000982953, ENST00000982954, ENST00000982955, ENST00001023996, ENST00001084871, ENST00001084872, ENST00001084873, ENST00001102901, ENST00001102902, ENST00001106839, ENST00001106840, ENST00001138253, ENST00001138254

RefSeq mRNA: 4 — MANE Select: NM_004985 NM_001369786, NM_001369787, NM_004985, NM_033360

CCDS: CCDS8702, CCDS8703

Canonical transcript exons

ENST00000311936 — 5 exons

Exon	Start	End
ENSE00000936617	25245274	25245395
ENSE00001644818	25225614	25225773
ENSE00001719809	25227234	25227412
ENSE00002456976	25205246	25209911
ENSE00003903543	25250751	25250929

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 97.68.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.4655 / max 2578.1531, expressed in 1786 samples.

Highest expression (Bgee): trigeminal ganglion, pylorus, nipple, oral cavity, mucosa of sigmoid colon.

Genetic regulation across tissues (GTEx eQTL / sQTL)

KRAS is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 19 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

19 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Colon Sigmoid	eqtl	1.0e-34	+0.79	12:25287791:A:G
Cells Cultured fibroblasts	eqtl	4.2e-14	-0.17	12:25186470:T:C
Colon Transverse	eqtl	8.6e-12	+0.30	12:25287791:A:G
Esophagus Muscularis	eqtl	3.0e-05	+0.23	12:25287791:A:G
Pancreas	eqtl	4.4e-05	-0.32	12:25254792:A:G
Esophagus Mucosa	eqtl	7.8e-05	-0.14	12:25368775:C:A
Thyroid	eqtl	1.7e-04	-0.12	12:25179908:T:C
Skin Sun Exposed Lower leg	eqtl	1.3e-03	+0.11	12:25150588:T:C
Nerve Tibial	eqtl	2.1e-03	+0.08	12:25365504:G:C
Pituitary	eqtl	3.6e-03	-0.17	12:25204694:TA:T
Brain Caudate basal ganglia	eqtl	3.9e-03	-0.17	12:25231904:G:A
Testis	eqtl	4.2e-03	+0.12	12:25384899:T:C
Whole Blood	eqtl	5.9e-03	+0.17	12:25884543:C:T
Lung	eqtl	7.5e-03	-0.11	12:25217524:GTCTTA:G
Skin Not Sun Exposed Suprapubic	eqtl	1.2e-02	+0.13	12:25147479:A:C
Minor Salivary Gland	eqtl	1.6e-02	+0.18	12:24911484:G:A
Heart Atrial Appendage	eqtl	2.2e-02	-0.19	12:25272448:G:A
Adrenal Gland	eqtl	3.3e-02	-0.30	12:25038750:C:A
Cells EBV-transformed lymphocytes	eqtl	3.8e-02	-0.19	12:25111017:G:T

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
130178	20.4655	1786

Top tissues by expression

showing 100 of 298 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
trigeminal ganglion	UBERON:0001675	97.68	gold quality
pylorus	UBERON:0001166	97.66	gold quality
nipple	UBERON:0002030	97.52	gold quality
oral cavity	UBERON:0000167	97.50	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.42	gold quality
esophagus squamous epithelium	UBERON:0006920	97.37	gold quality
pharyngeal mucosa	UBERON:0000355	97.14	gold quality
cardia of stomach	UBERON:0001162	97.13	gold quality
jejunal mucosa	UBERON:0000399	97.12	gold quality
tongue squamous epithelium	UBERON:0006919	97.03	gold quality
colonic mucosa	UBERON:0000317	96.92	gold quality
cauda epididymis	UBERON:0004360	96.75	gold quality
endothelial cell	CL:0000115	96.54	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.46	gold quality
dorsal root ganglion	UBERON:0000044	96.40	gold quality
superficial temporal artery	UBERON:0001614	96.24	gold quality
mammary duct	UBERON:0001765	96.20	gold quality
palpebral conjunctiva	UBERON:0001812	96.05	gold quality
superior surface of tongue	UBERON:0007371	96.03	gold quality
lower lobe of lung	UBERON:0008949	95.92	gold quality
olfactory bulb	UBERON:0002264	95.91	gold quality
epithelium of esophagus	UBERON:0001976	95.85	gold quality
corpus epididymis	UBERON:0004359	95.78	gold quality
renal medulla	UBERON:0000362	95.77	gold quality
cerebellar vermis	UBERON:0004720	95.75	gold quality
caput epididymis	UBERON:0004358	95.74	gold quality
pons	UBERON:0000988	95.69	gold quality
saphenous vein	UBERON:0007318	95.62	gold quality
upper leg skin	UBERON:0004262	95.60	gold quality
hair follicle	UBERON:0002073	95.42	gold quality
epithelium of mammary gland	UBERON:0003244	95.42	gold quality
parietal lobe	UBERON:0001872	95.10	gold quality
substantia nigra pars compacta	UBERON:0001965	95.04	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.99	gold quality
squamous epithelium	UBERON:0006914	94.95	gold quality
postcentral gyrus	UBERON:0002581	94.94	gold quality
middle temporal gyrus	UBERON:0002771	94.94	gold quality
skin of hip	UBERON:0001554	94.67	gold quality
vena cava	UBERON:0004087	94.63	gold quality
epithelium of nasopharynx	UBERON:0001951	94.48	gold quality
pericardium	UBERON:0002407	94.47	gold quality
superior vestibular nucleus	UBERON:0007227	94.42	gold quality
tibia	UBERON:0000979	94.37	gold quality
entorhinal cortex	UBERON:0002728	94.37	gold quality
synovial joint	UBERON:0002217	94.22	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.21	gold quality
visceral pleura	UBERON:0002401	94.20	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.11	gold quality
tongue	UBERON:0001723	94.06	gold quality
urethra	UBERON:0000057	93.94	gold quality
gingiva	UBERON:0001828	93.92	gold quality
trachea	UBERON:0003126	93.87	gold quality
orbitofrontal cortex	UBERON:0004167	93.84	gold quality
trabecular bone tissue	UBERON:0002483	93.81	gold quality
thymus	UBERON:0002370	93.79	gold quality
ventral tegmental area	UBERON:0002691	93.68	gold quality
medulla oblongata	UBERON:0001896	93.61	gold quality
amniotic fluid	UBERON:0000173	93.43	gold quality
jejunum	UBERON:0002115	93.43	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.38	gold quality
superior frontal gyrus	UBERON:0002661	93.27	gold quality
cranial nerve II	UBERON:0000941	92.96	gold quality
gingival epithelium	UBERON:0001949	92.85	gold quality
body of tongue	UBERON:0011876	92.83	gold quality
pleura	UBERON:0000977	92.62	gold quality
mammalian vulva	UBERON:0000997	92.47	gold quality
cortical plate	UBERON:0005343	92.47	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.44	gold quality
parietal pleura	UBERON:0002400	92.01	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.00	gold quality
penis	UBERON:0000989	91.98	gold quality
occipital lobe	UBERON:0002021	91.92	gold quality
Brodmann (1909) area 10	UBERON:0013541	91.87	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	91.83	gold quality
oviduct epithelium	UBERON:0004804	91.80	gold quality
inferior vagus X ganglion	UBERON:0005363	91.75	gold quality
bone marrow	UBERON:0002371	91.62	gold quality
frontal pole	UBERON:0002795	91.29	gold quality
pigmented layer of retina	UBERON:0001782	91.18	gold quality
retina	UBERON:0000966	91.16	gold quality
lateral globus pallidus	UBERON:0002476	91.05	gold quality
blood vessel layer	UBERON:0004797	91.04	gold quality
globus pallidus	UBERON:0001875	91.02	gold quality
mucosa of urinary bladder	UBERON:0001259	90.99	gold quality
cervix epithelium	UBERON:0004801	90.98	gold quality
paraflocculus	UBERON:0005351	90.97	gold quality
bronchial epithelial cell	CL:0002328	90.94	gold quality
medial globus pallidus	UBERON:0002477	90.93	gold quality
germinal epithelium of ovary	UBERON:0001304	90.79	gold quality
CA1 field of hippocampus	UBERON:0003881	90.73	gold quality
duodenum	UBERON:0002114	90.69	gold quality
rectum	UBERON:0001052	90.60	gold quality
mammary gland	UBERON:0001911	90.53	gold quality
thoracic mammary gland	UBERON:0005200	90.53	gold quality
primary visual cortex	UBERON:0002436	90.47	gold quality
biceps brachii	UBERON:0001507	90.40	gold quality
adult organism	UBERON:0007023	90.34	gold quality
endometrium	UBERON:0001295	90.27	gold quality
heart right ventricle	UBERON:0002080	90.21	gold quality
choroid plexus epithelium	UBERON:0003911	90.14	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	1869.04
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Cerebral cortex	tissue	54.4	medium
Motor cortex	tissue	54.4
Frontal cortex	tissue	53.6
Prefrontal cortex	tissue	52.6
Hippocampal formation	tissue	48.6
Entorhinal cortex	tissue	48.6
Retrosplenial and cingulate cortex	tissue	48.2
Retrosplenial cortex	tissue	47.0
Occipital cortex	tissue	47.0
Somatosensory cortex	tissue	46.7
Temporal cortex	tissue	43.2
Insular cortex	tissue	40.2
Olfactory bulb	tissue	39.8
Caudate putamen	tissue	37.2
Amygdala	tissue	37.1
Thalamus	tissue	36.7
Pons	tissue	34.9
Midbrain	tissue	33.4
Septum	tissue	32.2
Putamen	tissue	32.0
Ventral forebrain	tissue	31.4
Cerebellum	tissue	31.1	medium
Superior colliculi	tissue	30.6
Hypothalamus	tissue	29.8
Substantia nigra	tissue	27.1
Periaqueductal gray	tissue	26.7
Corpus callosum	tissue	26.5
Postcentral gyrus	tissue	26.3
Basal ganglia	tissue	26.1	not detected
Spinal cord	tissue	26.1
Medulla oblongata	tissue	25.3
Rectum	tissue	20.8	high
Colon	tissue	20.0	high
Locus coeruleus	tissue	19.9
Hippocampus	tissue	19.0	not detected
Stomach 1	tissue	18.5	medium
Small intestine	tissue	17.4	high
Esophagus	tissue	17.1	not detected
Retina	tissue	16.2
Bone marrow	tissue	16.1	medium
Tonsil	tissue	16.0	low
Nucleus accumbens	tissue	15.7
Thymus	tissue	15.4
Placenta	tissue	15.1	not detected
Urinary bladder	tissue	14.7	low
Lymph node	tissue	14.4	medium
Appendix	tissue	14.4	high
Liver	tissue	13.1	not detected
Duodenum	tissue	12.6	high
Smooth muscle	tissue	12.4	not detected
Gallbladder	tissue	11.3	high
Lung	tissue	11.0	not detected
Choroid plexus	tissue	10.6
Prostate	tissue	10.5	low
Adipose tissue	tissue	10.4	not detected
Parathyroid gland	tissue	10.3	medium
Spleen	tissue	10.2	not detected
Kidney	tissue	9.9	medium
Pancreas	tissue	9.7	low
Endometrium 1	tissue	9.5	not detected

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Dorsal hippocampus (45.9), Subiculum (42.3), Ventral hippocampus (39.9), Ventromedial nucleus (27.1), White matter (26.5).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets:

Target	Regulation
NFE2L2	Activation

Upstream regulators (CollecTRI, top): AR, ATF3, CEBPB, CTNNBL1, DMTF1, DNMT3B, EGR1, ESR1, ESX1, ETV3, FEZF1, FOXC1, GATA6, HESX1, HMGA1, HMGA2, HNF4A, HOXA9, HOXD1, HSF1, ID2, LRRFIP1, MAZ, MITF, MNT, MYB, MYC, NFE2L2, NKX3-1, NR0B2, NR3C1, PARP1, PAX6, PHF20, PITX1, POU1F1, RARA, RUNX1, SMAD6, SMARCC1

miRNA regulators (miRDB)

Targeting KRAS by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 327 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3185	99.99	68.12	1959

Functional genomics

gnomAD constraint: pLI 0.999, LOEUF 0.264, missense Z 3.09 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000311936 splits into 2 regions with different missense tolerance; 1 is missense-constrained (≈63% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
12:25,209,798–25,225,714	65 / 82.3	0.79	no
12:25,225,715–25,245,384	42 / 139.4	0.30	yes (p 1.6e-16)
DepMap (CRISPR cell-line fitness): dependent in 52.4% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): AsPC-1 (-4.461), Panc 08.13 (-3.968), RKN (-3.923), Panc 04.03 (-3.664), Calu-6 (-3.496), SNU-410 (-3.364), SU.86.86 (-3.346), SNU-61 (-3.334), PK-45H (-3.311), MIA PaCa-2 (-3.274), Panc 02.03 (-3.266), SUIT-2 (-3.18), SNU-1 (-3.136), HPAF-II (-3.119), SW 620 (-3.088).

Literature-anchored findings (GeneRIF, showing 40)

• It is proposed that lowering the affinity for GTP allows G12D Ras an escape from the oncogenic GTP-bound state, whereas GTP tightly bound to G12V mutant Ras generates a more persistent, potentially oncogenic, signal. (PMID:10398103)
• Mutations were detected by using allele-specific amplification method. (PMID:11524732)
• oncogenic levels of mitogen-activated protein kinase (MAPK) signaling of the dinucleotide KRAS2 mutations G12F and GG12-13VC (PMID:11668624)
• valine-12 Ki-Ras mutants demonstrated a greater ability to invade Matrigel than cells expressing the aspartate-12 mutant or wild-type Ki-Ras proteins. (PMID:11745690)
• KRAS2 mutations have been detected in laser-capture microdissected atypical endometrial hyperplasia specimens arising concurrently with endometrial carcinoma. (PMID:11746970)
• Ras modulates the proliferative response of RSF to TNF-alpha and TGF-alpha (PMID:11822784)
• mutations in K-ras have been detected in primary carcinoma of small intestine (PMID:11836595)
• Coordinated traffic of Grb2 and Ras during epidermal growth factor receptor endocytosis (PMID:12006650)
• K-ras mutations and RASSF1A promoter methylation in colorectal cancer (PMID:12032847)
• Multiple K-RAS mutations are frequent both in PC with associated PanIN and in biliary cancers, and indicate that clonally distinct precursor lesions of PC might variably contribute to tumor development. (PMID:12082617)
• Constitutive activation of NF-kappaB in Ki-ras-transformed prostate epithelial cells (PMID:12085227)
• Mutations in APC, Kirsten-ras, and p53–alternative genetic pathways to colorectal cancer. The most common combination of mutations was p53 and APC (27.1%), whereas mutations in both p53 and K-ras were extremely rare. (PMID:12093899)
• Uncommon mutation types of K-ras may contribute to long term patient survival in pancreatic adenocarcinoma. (PMID:12135058)
• study performed to determine the status of K-ras-2 in liver angiosarcomas (LAS) from workers occupationally exposed to vinyl chloride (PMID:12211074)
• Immunohistochemical staining of p21 appears to be of prognostic value in patients receiving systemic adjuvant chemotherapy for locally advanced bladder cancer. (PMID:12372883)
• the constitutive activation of Ras might have induced the persistent expression of p21cip1 and p27kip1, and that this induction of p21cip1 and p27kip1 expression possibly caused the cell cycle arrest at the G1 phase. (PMID:12452332)
• Review: Exploring environmental causes of altered ras effects: fragmentation plus integration? (PMID:12557259)
• Specific T-cell immunity against Ki-ras peptides in patients with pancreatic and colorectal cancers. (PMID:12592366)
• acute hyperglycemia-mediated mononuclear cell activation is dependent on activation of ras, p42/p44 mitogen-activated protein kinase phosphorylation, and subsequent NF-kappaB activation (PMID:12606501)
• LOH of chromosome 12p was seen in about 50% of human lung adenocarcinomas & large cell carcinomas. Kras2 mutations were seen at codon 12 in about 40% of adenocarcinomas & large cell carcinomas. The wild-type Kras2 is a tumor suppressor of lung cancer. (PMID:12606951)
• results demonstrate that the mutational status of BRAF and KRAS is distinctly different among histologic types of ovarian serous carcinoma, occurring most frequently in invasive micropapillary serous carcinomas and its precursors, serous borderline tumors (PMID:12644542)
• Ki-ras mutations and HGF signaling cooperate to enhance tumor growth by increased duration of MAPK activation and decreased apoptosis in human carcinoma cells. (PMID:12651912)
• results suggest that carcinogenesis in the biliary tract epithelium in anomalous pancreaticobiliary ductal union (APBDU) is accompanied by multistep genetic mutational events; K-ras gene mutation occurs early in epithelial hyperplasia or metaplasia (PMID:12720172)
• The results suggest a potential role for Ca2+/calmodulin in the regulation of K-RasB function. (PMID:12727204)
• No somatic mutations were identified in either TP53 or KRAS, indicating that disregulation of these genes is not required for leiomyomas development (PMID:12766905)
• types of mutations in sinonasal NK/T cell lymphoma in northeast district of China (PMID:12824925)
• codon 12 K-ras mutations in lung tumors or sputum samples from 102 lung cancer patients (PMID:12826308)
• p21Ras activation is instrumental in FVIIa signal transduction and the FVIIa-dependent activation of p21Ras involves either PKC or Src-dependent mechanisms, depending on the cell type investigated. (PMID:12871370)
• K-Ras4B polybasic domain or an alternatively prenylated CAAX renders Ras prenylation, Ras-induced Elk-1 activation, and anchorage-independent cell growth farnesyltransferase inhibitor-resistant. (PMID:12882980)
• Point mutations in Ki-ras gene is associated with colorectal cancers in mexican patients (PMID:12908779)
• signaling initiated by activated Ki-ras interferes with the IFN/STAT signaling pathway and modulates the responsiveness of cancer cells to interferons (PMID:12972432)
• K-ras mutations may have an effect on proliferation in pancreatic ductal adenocarcinoma (PMID:14508142)
• there is an inverse relationship between Kras2 activation and RASSF1A promoter methylation in the majority of human lung adenocarcinomas and large cell carcinomas (PMID:14511407)
• BRAF mutations, which are present in a variety of other human cancers, do not seem to be involved in gastric cancer development (PMID:14513361)
• KRAS2 mutations were seen in stomach neoplasms. (PMID:14534542)
• findings indicate the wild-type KRAS allele is occasionally lost in lung cancer and the oncogenic activation of mutant KRAS is more frequently associated with overexpression of the mutant allele than with loss of the wild-type allele in NSCLC development (PMID:14601056)
• The positive expression rates of p21 and p53 proteins were 75.0% and 57.3% respectively in pancreatic carcinoma, which were significantly different from those in the normal tissue (P<0.05). p21 and p53 proteins were positively correlated (P<0.05). (PMID:14612290)
• Oncogene Protein p21(ras) accumulation was confined to the upper layer of esophageal squamous cell carcinoma. (PMID:14654903)
• RAS or BRAF mutations are detected in about 32% of all Barrett’s adenocarcinomas; the disruption of the Raf/MEK/ERK (MAPK) kinase pathway is a frequent but also early event in the development of Barrett’s adenocarcinoma (PMID:14724583)
• Detection of P21 may be used as the screening marker for diagnosis of polycyclic aromatic hydrocarbons (PAHs)-related lung cancer related lung cancer, and may supplement the diagnostic value of conventional cytology. (PMID:14761400)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	kras	ENSDARG00000010844
mus_musculus	Kras	ENSMUSG00000030265
rattus_norvegicus	Kras	ENSRNOG00000081425

Paralogs (35): RALA (ENSG00000006451), REM1 (ENSG00000088320), RASL10A (ENSG00000100276), RASD2 (ENSG00000100302), RASL12 (ENSG00000103710), RHEB (ENSG00000106615), RASD1 (ENSG00000108551), RERGL (ENSG00000111404), RAP1A (ENSG00000116473), RASL11A (ENSG00000122035), RAP2C (ENSG00000123728), RAP2A (ENSG00000125249), RRAS (ENSG00000126458), RAP1B (ENSG00000127314), RASL11B (ENSG00000128045), RRAS2 (ENSG00000133818), RERG (ENSG00000134533), REM2 (ENSG00000139890), RIT1 (ENSG00000143622), RALB (ENSG00000144118), RIT2 (ENSG00000152214), MRAS (ENSG00000158186), DIRAS3 (ENSG00000162595), GEM (ENSG00000164949), DIRAS2 (ENSG00000165023), RRAD (ENSG00000166592), RHEBL1 (ENSG00000167550), NKIRAS2 (ENSG00000168256), HRAS (ENSG00000174775), DIRAS1 (ENSG00000176490), RAP2B (ENSG00000181467), ERAS (ENSG00000187682), NKIRAS1 (ENSG00000197885), NRAS (ENSG00000213281), RASL10B (ENSG00000270885)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:96680) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 204 distinct phenotype terms.

Mouse phenotype (MP)	Records
premature death	16
increased lung adenoma incidence	14
increased pancreatic intraepithelial neoplasia incidence	12
increased lung adenocarcinoma incidence	11
increased lung tumor incidence	11
anemia	6
enlarged spleen	5
increased skin papilloma incidence	5
increased pancreatic ductal adenocarcinoma incidence	5
increased leukocyte cell number	4
increased cell proliferation	4
increased papilloma incidence	4
increased tumor incidence	3
pallor	3
abnormal large intestine crypts of Lieberkuhn morphology	3
increased lung non-small cell carcinoma incidence	3
increased pancreas tumor incidence	3
embryonic lethality during organogenesis, complete penetrance	3
extramedullary hematopoiesis	2
abnormal erythropoiesis	2
abnormal heart morphology	2
abnormal colon morphology	2
liver hypoplasia	2
prostate gland hyperplasia	2
abnormal brain development	2

+179 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pan troglodytes	A5A6J7	100.0%	Diamond
Coprinopsis cinerea okayama7#130	A8NU18	100.0%	Diamond
Drosophila ananassae	B3M185	100.0%	Diamond
Drosophila erecta	B3NZR4	100.0%	Diamond
Drosophila persimilis	B4GFJ8	100.0%	Diamond
Drosophila sechellia	B4HKC7	100.0%	Diamond
Drosophila yakuba	B4PUP5	100.0%	Diamond
Crocodylus siamensis	C0HM48	100.0%	Diamond
Gallus gallus	P08642	100.0%	Diamond
Drosophila melanogaster	P08646	100.0%	Diamond
Cryptococcus deneoformans JEC21	P0CQ42	100.0%	Diamond
Cryptococcus deneoformans B-3501A	P0CQ43	100.0%	Diamond
Candida albicans	P0CY32	100.0%	Diamond
Bos taurus	P61223	100.0%	Diamond
Saguinus oedipus	P63320	100.0%	Diamond
Drosophila simulans	P83831	100.0%	Diamond
Drosophila mauritiana	P83832	100.0%	Diamond
Coprinopsis cinerea	Q05058	100.0%	Diamond
Sus scrofa	Q06AU2	100.0%	Diamond
Drosophila pseudoobscura pseudoobscura	Q295X7	100.0%	Diamond
Macaca fascicularis	Q4R9D4	100.0%	Diamond
Candida albicans SC5314	Q59XU5	100.0%	Diamond
Pongo abelii	Q5R4B8	100.0%	Diamond
Mesocricetus auratus	Q60529	100.0%	Diamond
Xenopus tropicalis	Q640R7	100.0%	Diamond
Xenopus laevis	Q7ZXH7	100.0%	Diamond
Drosophila grimshawi	B4JFU8	99.5%	Diamond
Drosophila virilis	B4LY29	99.5%	Diamond
Cavia porcellus	P12825	99.5%	Diamond
Candida albicans WO-1	C4YKT4	99.0%	Diamond
Oryzias latipes	O42277	99.0%	Diamond
Carassius auratus	P05774	99.0%	Diamond
Meleagris gallopavo	P79800	99.0%	Diamond
Monodelphis domestica	Q07983	99.0%	Diamond
Kryptolebias marmoratus	Q5EFX7	99.0%	Diamond
Cyprinus carpio	Q9YH38	99.0%	Diamond
NS.C58 murine sarcoma virus	P23175	99.5%	Diamond
Moloney murine sarcoma virus	P01113	99.0%	Diamond
Rasheed rat sarcoma virus	P01114	99.0%	Diamond
Harvey murine sarcoma virus	P01115	98.9%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ETFRF1	protein-coding	144363
IRAG2	protein-coding	4033
DNAI7	protein-coding	55259
LINC02909	ncRNA	196415

Protein

Protein identifiers

GTPase KRas — P01116 (reviewed: P01116)

Alternative names: K-Ras 2, Ki-Ras, c-K-ras, c-Ki-ras

All UniProt accessions (11): A0A8I5KQ21, A0A8I5KQU3, A0A8I5KR86, A0A8I5KUB5, A0A8I5KXN3, A0A8I5KYH6, A0ABF7PHA5, G3V4K2, G3V5T7, P01116, L7RSL8

UniProt curated annotations — full annotation on UniProt →

Function. Signal transducer in the Ras-MAPK signaling pathway that regulates cell proliferation and survival. Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Activates MAPK1/MAPK3 resulting in phosphorylation and ultimately degradation of GJA1. Plays a role in promoting oncogenic events by inducing transcriptional silencing of tumor suppressor genes (TSGs) in colorectal cancer (CRC) cells in a ZNF304-dependent manner. Recognized by LZTR1 that mediates its ubiquitination by a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex.

Subunit / interactions. Interacts with PHLPP. Interacts (active GTP-bound form preferentially) with RGS14. Interacts (when farnesylated) with PDE6D; this promotes dissociation from the cell membrane. Interacts with SOS1. Interacts (when farnesylated) with GPR31. Interacts with RAP1GDS1. Interacts (active GTP-bound form) with both SHOC2 and PP1c (all isoforms) to form a tertiary complex; SHOC2 and PP1c preferably bind M-Ras/MRAS, but they also bind K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS. Interacts (GTP-bound form) with MAPKAP1/SIN1; inhibiting K-Ras/KRAS activity. Interacts (GDP-bound form) with LZTR1; this interaction mediates KRAS ubiquitination by BCR E3 ligase complex. Interacts with GPR31; in a farnelysation-dependent manner.

Subcellular location. Cell membrane. Endomembrane system. Cytoplasm Cell membrane.

Tissue specificity. Expressed throughout the epidermis, but weakly expressed in the stratum corneum and dermis (at protein level).

Post-translational modifications. Acetylation at Lys-104 prevents interaction with guanine nucleotide exchange factors (GEFs). Palmitoylated at Lys-182, Lys-184 and Lys-185. Palmitoylation on lysine residues is promoted by palmitoylation at Cys-180. Lysine-depalmitoylation by SIRT2 promotes its localization to endomembranes in endocytic pathways. Ubiquitinated by the BCR(LZTR1) E3 ubiquitin ligase complex at Lys-170 in a non-degradative manner, leading to inhibit Ras signaling by decreasing Ras association with membranes. (Microbial infection) Glucosylated at Thr-35 by P.sordellii toxin TcsL.

Disease relevance. Leukemia, acute myelogenous (AML) [MIM:601626] A subtype of acute leukemia, a cancer of the white blood cells. AML is a malignant disease of bone marrow characterized by maturational arrest of hematopoietic precursors at an early stage of development. Clonal expansion of myeloid blasts occurs in bone marrow, blood, and other tissue. Myelogenous leukemias develop from changes in cells that normally produce neutrophils, basophils, eosinophils and monocytes. The disease is caused by variants affecting the gene represented in this entry. Leukemia, juvenile myelomonocytic (JMML) [MIM:607785] An aggressive pediatric myelodysplastic syndrome/myeloproliferative disorder characterized by malignant transformation in the hematopoietic stem cell compartment with proliferation of differentiated progeny. Patients have splenomegaly, enlarged lymph nodes, rashes, and hemorrhages. The disease is caused by variants affecting the gene represented in this entry. Noonan syndrome 3 (NS3) [MIM:609942] A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. The disease is caused by variants affecting the gene represented in this entry. Gastric cancer (GASC) [MIM:613659] A malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease. The disease is caused by variants affecting the gene represented in this entry. Defects in KRAS are a cause of pylocytic astrocytoma (PA). Pylocytic astrocytomas are neoplasms of the brain and spinal cord derived from glial cells which vary from histologically benign forms to highly anaplastic and malignant tumors. Cardiofaciocutaneous syndrome 2 (CFC2) [MIM:615278] A form of cardiofaciocutaneous syndrome, a multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and intellectual disability. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. CFC2 patients often do not have the skin abnormalities, such as ichthyosis, hyperkeratosis, and hemangioma observed in CFC1. The disease is caused by variants affecting the gene represented in this entry. KRAS mutations are involved in cancer development. Oculoectodermal syndrome (OES) [MIM:600268] A syndrome characterized by the association of epibulbar dermoids and aplasia cutis congenita. Affected individuals show multiple, asymmetric, atrophic, non-scarring and hairless regions that may be associated with hamartomas. Ectodermal changes include linear hyperpigmentation that may follow the lines of Blaschko and rarely epidermal nevus-like lesions. Epibulbar dermoids may be uni-or bilateral. Additional ocular anomalies such as skin tags of the upper eyelid, rarely optic nerve or retinal changes, and microphthalmia can be present. The phenotypic expression is highly variable, and various other abnormalities have occasionally been reported including growth failure, lymphedema, cardiovascular defects, as well as neurodevelopmental symptoms like developmental delay, epilepsy, learning difficulties, and behavioral abnormalities. Benign tumor-like lesions such as nonossifying fibromas of the long bones and giant cell granulomas of the jaws have repeatedly been observed and appear to be age-dependent, becoming a common manifestation in individuals aged 5 years or older. The disease is caused by variants affecting the gene represented in this entry. Schimmelpenning-Feuerstein-Mims syndrome (SFM) [MIM:163200] A disease characterized by sebaceous nevi, often on the face, associated with variable ipsilateral abnormalities of the central nervous system, ocular anomalies, and skeletal defects. Many oral manifestations have been reported, not only including hypoplastic and malformed teeth, and mucosal papillomatosis, but also ankyloglossia, hemihyperplastic tongue, intraoral nevus, giant cell granuloma, ameloblastoma, bone cysts, follicular cysts, oligodontia, and odontodysplasia. Sebaceous nevi follow the lines of Blaschko and these can continue as linear intraoral lesions, as in mucosal papillomatosis. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Alternates between an inactive form bound to GDP and an active form bound to GTP. Activated by a guanine nucleotide-exchange factor (GEF) and inactivated by a GTPase-activating protein (GAP). Interaction with SOS1 promotes exchange of bound GDP to GTP.

Similarity. Belongs to the small GTPase superfamily. Ras family.

Isoforms (2)

UniProt ID	Names	Canonical?
P01116-1	2A, K-Ras4A	yes
P01116-2	2B, K-Ras4B

RefSeq proteins (4): NP_001356715, NP_001356716, NP_004976, NP_203524 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR020849	Small_GTPase_Ras-type	Family
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00071

Enzyme classification (BRENDA)

• EC 3.6.5.2 — small monomeric GTPase (BRENDA: 49 organisms, 138 substrates, 55 inhibitors, 5 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	—	0

Catalyzed reactions (Rhea)

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (100 total): sequence variant 34, binding site 17, strand 11, helix 10, mutagenesis site 8, lipid moiety-binding region 5, modified residue 4, chain 2, splice variant 2, initiator methionine 1, propeptide 1, glycosylation site 1, cross-link 1, region of interest 1, short sequence motif 1, turn 1

Structure

Experimental structures (PDB)

showing 30 of 549 structures by resolution:

PDB	Title	Method	Resolution (Å)
9IAY	Structure of 10 in complex with GDP-KRAS	X-RAY DIFFRACTION	0.95
9IAW	Structure of 5 in complex with GDP-KRAS	X-RAY DIFFRACTION	1
12XE	Crystal structure of KRAS(Q61K) bound to GppNHp and ligand	X-RAY DIFFRACTION	1.01
8ONV	KRAS-G13D in complex with BI-2493	X-RAY DIFFRACTION	1.01
6P0Z	Crystal structure of N-acetylated KRAS (2-169) bound to GDP and Mg	X-RAY DIFFRACTION	1.01
9IB5	Structure of 18 (BI-2493) in complex with GDP-KRAS	X-RAY DIFFRACTION	1.01
8AZZ	KRAS-G12V in complex with BI-2865	X-RAY DIFFRACTION	1.02
8AZX	KRAS-G12C in complex with BI-2865	X-RAY DIFFRACTION	1.04
8B00	KRAS-G13D in complex with BI-2865	X-RAY DIFFRACTION	1.04
8TVK	KRAS 1-169 G12C Mutant at 100k	X-RAY DIFFRACTION	1.04
4QL3	Crystal Structure of a GDP-bound G12R Oncogenic Mutant of Human GTPase KRas	X-RAY DIFFRACTION	1.04
8AZV	KRAS in complex with BI-2865	X-RAY DIFFRACTION	1.05
9IB4	Structure of 12 in complex with GDP-KRAS	X-RAY DIFFRACTION	1.06
9E3S	Tricomplex of RMC-9945, KRAS G12N, and CypA	X-RAY DIFFRACTION	1.08
8AZY	KRAS-G12D in complex with BI-2865	X-RAY DIFFRACTION	1.09
12LA	Crystal structure of human KRAS G12C covalently bound to 4-methyl-thiazol-5-yl piperidine …	X-RAY DIFFRACTION	1.1
8B78	KRasG12C ligand complex	X-RAY DIFFRACTION	1.11
9N44	Crystal structure of human KRAS-G12C covalent bound to Olomorasib	X-RAY DIFFRACTION	1.11
8AFB	CRYSTAL STRUCTURE OF KRAS-G12C IN COMPLEX WITH COMPOUND 23 (BI-0474)	X-RAY DIFFRACTION	1.12
8FMI	Crystal structure of human KRAS at 1.12 A	X-RAY DIFFRACTION	1.12
9YMP	Crystal Structure of human KRAS G12D in complex with GMPPCP and AM-2383	X-RAY DIFFRACTION	1.12
4TQA	Crystal Structure of a GDP-bound G13D Oncogenic Mutant of Human GTPase KRas	X-RAY DIFFRACTION	1.13
9BG4	Tri-complex of Compound-2, KRAS G12V, and CypA	X-RAY DIFFRACTION	1.14
9G4B	Human KRas4A (GDP) in complex with compound 15	X-RAY DIFFRACTION	1.14
4LDJ	Crystal Structure of a GDP-bound G12C Oncogenic Mutant of Human GTPase KRas	X-RAY DIFFRACTION	1.15
6TAN	X-RAY STRUCTURE OF HUMAN K-RAS G12C IN COMPLEX WITH COVALENT ISOQUINOLINONE INHIBITOR …	X-RAY DIFFRACTION	1.16
8R7W	Kras G12D in complex with compound 3	X-RAY DIFFRACTION	1.16
7O70	KRasG12C ligand complex	X-RAY DIFFRACTION	1.18
8EDY	KRAS4b A146T 1-185 bound to GDP	X-RAY DIFFRACTION	1.18
8EER	KRAS4B A146V 1-185 bound to GDP	X-RAY DIFFRACTION	1.18

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01116-F1	91.65	0.78

Antibody-complex structures (SAbDab)

11 antibodies co-crystallized with this protein: 7MDP, 7RP2, 7RP3, 7STF, 7YV1, 8BE5, 8UDR, 8VR9, 8VRA, 8VRB, 9I5E

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Predicted intracellular proteins, RAS pathway related proteins, Cancer-related genes, Candidate cancer biomarkers, Mutated cancer genes, Mutational cancer driver genes, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes, Congenital malformations, Other congenital malformations

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol

Antibody reliability (HPA): IH approved · IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (17)

Position	Role
17	GTP
17	Mg(2+)
18	GTP
28	GTP
29	GTP
30	GTP
57	Mg(2+)
116	GTP
117	GTP
119	GTP
145	GTP
146	GTP
147	GTP
13	GTP
14	GTP
15	GTP
16	GTP

Post-translational modifications (10)

Type	Positions
N-acetylmethionine	1
N-acetylthreonine	2
N6-acetyllysine	104
Cysteine methyl ester	186
S-palmitoyl cysteine	180
N6-palmitoyl lysine	182, 184, 185
S-farnesyl cysteine	186
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in ubiquitin)	170

Glycosylation sites (1)

Type	Positions
(microbial infection) o-linked (glc) threonine	35

Mutagenesis-validated functional residues (8)

Position	Phenotype
35	increases affinity for lztr1; alone and when associated with a-62.
38	decreased interaction with mapkap1/sin1.
40	decreased interaction with mapkap1/sin1.
61	promotes gtp binding.
62	increases affinity for lztr1; alone and when associated with a-35.
180	abolished palmitoylation on cys; reduced palmitoylation on lys residues.
182–185	in k-ras-3kr; abolished lysine-palmitoylation.
185	abolished interaction with gpr131.

Function

Pathways and Gene Ontology

Reactome pathways

57 curated (TAS) of 85; 29 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

showing 60 of 85 pathways:

ID	Pathway	Evidence
R-HSA-5637810	Constitutive Signaling by EGFRvIII ⚕	curated
R-HSA-1236382	Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants ⚕	curated
R-HSA-9634285	Constitutive Signaling by Overexpressed ERBB2 ⚕	curated
R-HSA-6802955	Paradoxical activation of RAF signaling by kinase inactive BRAF ⚕	curated
R-HSA-6802953	RAS signaling downstream of NF1 loss-of-function variants ⚕	curated
R-HSA-6802952	Signaling by BRAF and RAF1 fusions ⚕	curated
R-HSA-9665348	Signaling by ERBB2 ECD mutants ⚕	curated
R-HSA-9664565	Signaling by ERBB2 KD Mutants ⚕	curated
R-HSA-9665686	Signaling by ERBB2 TMD/JMD mutants ⚕	curated
R-HSA-5655302	Signaling by FGFR1 in disease ⚕	curated
R-HSA-5655253	Signaling by FGFR2 in disease ⚕	curated
R-HSA-5655332	Signaling by FGFR3 in disease ⚕	curated
R-HSA-5655291	Signaling by FGFR4 in disease ⚕	curated
R-HSA-9703648	Signaling by FLT3 ITD and TKD mutants ⚕	curated
R-HSA-9703465	Signaling by FLT3 fusion proteins ⚕	curated
R-HSA-9673770	Signaling by PDGFRA extracellular domain mutants ⚕	curated
R-HSA-9673767	Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants ⚕	curated
R-HSA-9656223	Signaling by RAF1 mutants ⚕	curated
R-HSA-9753510	Signaling by RAS GAP mutants ⚕	curated
R-HSA-9753512	Signaling by RAS GTPase mutants ⚕	curated
R-HSA-6802948	Signaling by high-kinase activity BRAF mutants ⚕	curated
R-HSA-6802946	Signaling by moderate kinase activity BRAF mutants ⚕	curated
R-HSA-9670439	Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants ⚕	curated
R-HSA-9649948	Signaling downstream of RAS mutants ⚕	curated
R-HSA-1169092	Activation of RAS in B cells	curated
R-HSA-5621575	CD209 (DC-SIGN) signaling	curated
R-HSA-4086398	Ca2+ pathway	curated
R-HSA-2424491	DAP12 signaling	curated
R-HSA-186763	Downstream signal transduction	curated
R-HSA-2179392	EGFR Transactivation by Gastrin	curated
R-HSA-9634635	Estrogen-stimulated signaling through PRKCZ	curated
R-HSA-2871796	FCERI mediated MAPK activation	curated
R-HSA-9607240	FLT3 Signaling	curated
R-HSA-5654693	FRS-mediated FGFR1 signaling	curated
R-HSA-5654700	FRS-mediated FGFR2 signaling	curated
R-HSA-5654706	FRS-mediated FGFR3 signaling	curated
R-HSA-5654712	FRS-mediated FGFR4 signaling	curated
R-HSA-179812	GRB2 events in EGFR signaling	curated
R-HSA-5674135	MAP2K and MAPK activation	curated
R-HSA-8851805	MET activates RAS signaling	curated
R-HSA-375165	NCAM signaling for neurite out-growth	curated
R-HSA-5675221	Negative regulation of MAPK pathway	curated
R-HSA-8849471	PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	curated
R-HSA-5673000	RAF activation	curated
R-HSA-9648002	RAS processing	curated
R-HSA-8951936	RUNX3 regulates p14-ARF	curated
R-HSA-5658442	Regulation of RAS by GAPs	curated
R-HSA-5654688	SHC-mediated cascade:FGFR1	curated
R-HSA-5654699	SHC-mediated cascade:FGFR2	curated
R-HSA-5654704	SHC-mediated cascade:FGFR3	curated
R-HSA-5654719	SHC-mediated cascade:FGFR4	curated
R-HSA-180336	SHC1 events in EGFR signaling	curated
R-HSA-1250347	SHC1 events in ERBB4 signaling	curated
R-HSA-9674555	Signaling by CSF3 (G-CSF)	curated
R-HSA-1433557	Signaling by SCF-KIT	curated
R-HSA-210993	Tie2 Signaling	curated
R-HSA-5218921	VEGFR2 mediated cell proliferation	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers ⚕	—
R-HSA-6802957	Oncogenic MAPK signaling ⚕	—

MSigDB gene sets: 0 (showing top):

GO Biological Process (20): MAPK cascade (GO:0000165), liver development (GO:0001889), Ras protein signal transduction (GO:0007265), female pregnancy (GO:0007565), positive regulation of cell population proliferation (GO:0008284), response to gravity (GO:0009629), positive regulation of gene expression (GO:0010628), cytokine-mediated signaling pathway (GO:0019221), response to isolation stress (GO:0035900), positive regulation of Ras protein signal transduction (GO:0046579), response to glucocorticoid (GO:0051384), response to mineralocorticoid (GO:0051385), myoblast proliferation (GO:0051450), cardiac muscle cell proliferation (GO:0060038), positive regulation of cellular senescence (GO:2000774), signal transduction (GO:0007165), positive regulation of TOR signaling (GO:0032008), regulation of cell population proliferation (GO:0042127), negative regulation of programmed cell death (GO:0043069), positive regulation of MAPK cascade (GO:0043410)

GO Molecular Function (12): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), GMP binding (GO:0019002), GDP binding (GO:0019003), LRR domain binding (GO:0030275), identical protein binding (GO:0042802), protein-membrane adaptor activity (GO:0043495), protein-containing complex binding (GO:0044877), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (10): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), mitochondrial outer membrane (GO:0005741), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cytoplasmic side of plasma membrane (GO:0009898), membrane (GO:0016020), endomembrane system (GO:0012505)

Reactome top-level categories

16 top-level categories:

Category	Pathways
Oncogenic MAPK signaling	2
Cytokine Signaling in Immune system	2
RAS GTPase cycle mutants	2
Signaling by EGFR	2
Transcriptional regulation by RUNX3	1
RAF/MAP kinase cascade	1
Signaling by RAS mutants	1
IRS-mediated signalling	1
Downstream signaling events of B Cell Receptor (BCR)	1
Signaling by Ligand-Responsive EGFR Variants in Cancer	1
Signaling by ERBB2	1
Signaling by ERBB4	1
Signaling by Receptor Tyrosine Kinases	1
Signalling to ERKs	1
Signalling to RAS	1
Signaling by PDGF	1

GO top-level categories

showing 60 of 66 GO namespaces:

Category	Terms
cellular anatomical structure	4
cell population proliferation	3
guanyl ribonucleotide binding	3
anion binding	3
positive regulation of cellular process	2
response to corticosteroid	2
regulation of cellular process	2
positive regulation of intracellular signal transduction	2
binding	2
plasma membrane	2
intracellular signaling cassette	1
gland development	1
hepaticobiliary system development	1
small GTPase-mediated signal transduction	1
multi-organism reproductive process	1
multi-multicellular organism process	1
regulation of cell population proliferation	1
response to abiotic stimulus	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
multicellular organismal response to stress	1
Ras protein signal transduction	1
regulation of Ras protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
striated muscle cell proliferation	1
cardiac muscle tissue growth	1
cellular senescence	1
regulation of cellular senescence	1
cell communication	1
cellular process	1
signaling	1
cellular response to stimulus	1
TOR signaling	1
regulation of TOR signaling	1
programmed cell death	1
regulation of programmed cell death	1
negative regulation of cellular process	1
MAPK cascade	1
regulation of MAPK cascade	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
molecular function regulator activity	1
purine ribonucleoside triphosphate binding	1
protein domain specific binding	1
protein binding	1
protein-macromolecule adaptor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
intracellular anatomical structure	1
mitochondrial membrane	1
organelle outer membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 10 of 42 annotations. The rest are phylogenetic / computational / electronic (IEA).

10 experimentally-supported GO terms:

GO term	NS	Evidence
positive regulation of gene expression	BP	mutant phenotype
cytoplasm	CC	direct assay
cytoplasmic side of plasma membrane	CC	direct assay
cytosol	CC	direct assay
focal adhesion	CC	high-throughput assay
membrane	CC	high-throughput assay
plasma membrane	CC	direct assay
GTPase activity	MF	mutant phenotype
identical protein binding	MF	physical interaction
protein-containing complex binding	MF	direct assay

Protein interactions and networks

STRING

showing 16 of 8,288 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KRAS	BRAF	P15056	975
KRAS	TP53	P04637	950
KRAS	PIK3CA	P42336	929
KRAS	ERBB2	P04626	920
KRAS	EGFR	P00533	917
KRAS	PTEN	P60484	917
KRAS	CDKN2A	P42771	910
KRAS	SMAD4	Q13485	900
KRAS	PTPN11	Q06124	884
KRAS	ALK	Q9UM73	882
KRAS	ROS1	P08922	880
KRAS	MAP2K1	Q02750	871
KRAS	STK11	Q15831	871
KRAS	NF1	P21359	869
KRAS	ARID1A	O14497	864
KRAS	AKT1	P31749	864

IntAct

Human interaction partners of KRAS in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 53 partners by confidence:

Partner	Interaction type	MIscore	Records
RAF1	physical association	0.690	2
BRAF	association	0.680	2
PIP5K1A	physical association	0.660	8
ARAF	physical association	0.560	3
RASSF2	physical association	0.540	2
ARL6IP5	physical association	0.520	1
RHOA	physical association	0.520	1
SHOC2	physical association	0.400	1
ADH6	physical association	0.370	1
BCAS3	physical association	0.370	1
CCL5	physical association	0.370	1
CCT7	physical association	0.370	1
CDK8	physical association	0.370	1
DDX47	physical association	0.370	1
DDX50	physical association	0.370	1
DEAF1	physical association	0.370	1
DIRAS3	physical association	0.370	1
EEF1A1	physical association	0.370	1
EGLN1	physical association	0.370	1
FANCC	physical association	0.370	1
FRAT2	physical association	0.370	1
HEMGN	physical association	0.370	1
HNRNPC	physical association	0.370	1
IGFBP3	physical association	0.370	1
IGSF21	physical association	0.370	1
IL24	physical association	0.370	1
LPAR1	physical association	0.370	1
LYPD4	physical association	0.370	1
MOCS2	physical association	0.370	1
MT-CO3	physical association	0.370	1

BioGRID (4,295 interactions; top human partners by supporting records in a sample of 600 records): RAF1 (Affinity Capture-MS; 6 records), BRAF (Affinity Capture-MS; 3 records), HNRNPC (Two-hybrid; 3 records), ARAF (Two-hybrid; 2 records), CTNNB1 (Affinity Capture-MS; 2 records), DIRAS3 (Synthetic Growth Defect; 2 records), EEF1A1 (Synthetic Lethality; 2 records), EPRS (Synthetic Lethality; 2 records), ERH (Synthetic Lethality; 2 records), GATAD2A (Synthetic Lethality; 2 records), GSPT1 (Synthetic Lethality; 2 records), HSPA9 (Synthetic Lethality; 2 records), HSPD1 (Synthetic Lethality; 2 records), MAP2K1 (Synthetic Growth Defect; 2 records), NCL (Synthetic Lethality; 2 records)

SIGNOR signaling

showing 40 of 46 signaling interactions:

A	Effect	B	Mechanism
RIN1	up-regulates	KRAS	binding
SOS1	up-regulates	KRAS	“guanine nucleotide exchange factor”
KRAS	up-regulates	RAF1	binding
KRAS	up-regulates	MINK1
KRAS	“up-regulates activity”	BRAF	binding
RASGEF1C	up-regulates	KRAS	binding
RAP1GDS1	up-regulates	KRAS	binding
KRAS	up-regulates	PIK3CA	binding
KRAS	up-regulates	PIK3CB	binding
KRAS	up-regulates	PIK3CD	binding
KRAS	up-regulates	PIK3CG	binding
SOS2	up-regulates	KRAS	“guanine nucleotide exchange factor”
RAPGEF5	up-regulates	KRAS	“guanine nucleotide exchange factor”
RASGEF1A	up-regulates	KRAS	“guanine nucleotide exchange factor”
RASGEF1B	up-regulates	KRAS	binding
FNTB	“up-regulates activity”	KRAS
FNTA	“up-regulates activity”	KRAS
KRAS	“up-regulates activity”	RASSF1	binding
RASSF5	“up-regulates activity”	KRAS	binding
KRAS	up-regulates	PI3K	binding
EML4-ALK	up-regulates	KRAS
DAB2IP	“down-regulates activity”	KRAS	“gtpase-activating protein”
PTPN11	“up-regulates activity”	KRAS	dephosphorylation
KRAS	up-regulates	Glycolysis
KRAS	“up-regulates quantity by expression”	NFE2L2	“transcriptional regulation”
KRAS	“down-regulates activity”	CARM1
LZTR1	“down-regulates activity”	KRAS	ubiquitination
LZTR1	“down-regulates quantity”	KRAS	ubiquitination
EFR3A	“up-regulates quantity”	KRAS	binding
TRiC	“up-regulates quantity by stabilization”	KRAS	binding
NF1	“down-regulates activity”	KRAS	binding
PTPN2	“down-regulates activity”	KRAS	dephosphorylation
“Av/b3 integrin”	“up-regulates activity”	KRAS	binding
KRAS	“up-regulates activity”	V-ATPase	relocalization
SRC	“up-regulates activity”	KRAS	phosphorylation
KRAS	up-regulates	MAP3K1	binding
SRC	up-regulates	KRAS	phosphorylation
KRAS	up-regulates	MAP4K5
KRAS	up-regulates	NFIL3
MVD	“up-regulates quantity by stabilization”	KRAS

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
★ KRAS-PPP1CC-SHOC2 complex	3	KRAS, PPP1CC, SHOC2
★ AGO2-KRAS complex	2	AGO2, KRAS
★ KRAS-RNF141 complex	2	KRAS, RNF141

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 53 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
RAF activation	5	41.0×	1e-05
RAF/MAP kinase cascade	6	8.9×	3e-03

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

Mutations in the RAS family of proteins are frequently observed across cancer types. The amino acid positions that account for the overwhelming majority of these mutations are G12, G13 and Q61. The different protein isoforms, despite their raw similarity, also behave very differently when expressed in non-native tissue types, likely due to differences in the C-terminal hyper-variable regions. Mis-regulation of isoform expression has been shown to be a driving event in cancer, as well as missense mutations at the three hotspots previously mentioned. While highly recurrent in cancer, attempts to target these RAS mutants with inhibitors have not been successful, and has not yet become common practice in the clinic. The prognostic implications for KRAS mutations vary between cancer types, but have been shown to be associated with poor outcome in colorectal cancer, non-small cell lung cancer, and others.

From intOGen — cancer-driver classification: activating (oncogene-like) across 36 cancer types — ALL, AML, ANSC, BLADDER, BLCA, BRCA, CEAD, CESC, CHOL, CLLSLL, COAD, COADREAD…(+24 more).

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for KRAS: 581 ClinVar records (85 pathogenic / likely pathogenic); 15 ClinGen expert-panel interpretations; 29 CIViC cancer variants; 2 PharmGKB clinical annotations; 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

581 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	39
Likely pathogenic	46
Uncertain significance	208
Likely benign	174
Benign	35

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 85 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
12589	NM_004985.5(KRAS):c.40G>A (p.Val14Ile)	Pathogenic	reviewed by expert panel	26
12587	NM_004985.5(KRAS):c.458A>T (p.Asp153Val)	Pathogenic	reviewed by expert panel	19
40452	NM_004985.5(KRAS):c.65A>G (p.Gln22Arg)	Pathogenic	reviewed by expert panel	14
12586	NM_004985.5(KRAS):c.178G>C (p.Gly60Arg)	Pathogenic	reviewed by expert panel	10
40454	NM_004985.5(KRAS):c.101C>T (p.Pro34Leu)	Pathogenic	reviewed by expert panel	9
12588	NM_004985.5(KRAS):c.173C>T (p.Thr58Ile)	Pathogenic	reviewed by expert panel	7
12594	NM_033360.4(KRAS):c.15A>T (p.Lys5Asn)	Pathogenic	reviewed by expert panel	4
438796	NM_033360.4(KRAS):c.194G>T (p.Ser65Ile)	Likely pathogenic	reviewed by expert panel	4
12580	NM_004985.5(KRAS):c.38G>A (p.Gly13Asp)	Pathogenic	criteria provided, multiple submitters, no conflicts	29
12583	NM_004985.5(KRAS):c.35G>T (p.Gly12Val)	Pathogenic	criteria provided, multiple submitters, no conflicts	20
12584	NM_004985.5(KRAS):c.34G>A (p.Gly12Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	15
12597	NM_033360.4(KRAS):c.178G>A (p.Gly60Ser)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
375965	NM_033360.4(KRAS):c.351A>C (p.Lys117Asn)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
12595	NM_033360.4(KRAS):c.*22C>G	Pathogenic	criteria provided, multiple submitters, no conflicts	4
45117	NM_004985.5(KRAS):c.183A>T (p.Gln61His)	Pathogenic	criteria provided, multiple submitters, no conflicts	4

Per-variant reference — Sugi Variant

Explore KRAS’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

ClinGen expert-panel interpretations (15)

Expert ACMG interpretations from RASopathy VCEP for Noonan syndrome; RASopathy; cardiofaciocutaneous syndrome — a higher-authority tier than individual ClinVar submissions.

Assertion	Variants
Pathogenic	7
Likely Pathogenic	1
Uncertain Significance	1
Likely Benign	3
Benign	3

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 30 predictions of 612):

Position(s)	Effect	Δscore	Sites
12:25209912–25209913	acceptor_loss	1.0000	6
12:25225612–25225613	donor_loss	1.0000	3
12:25225774–25225775	acceptor_loss	1.0000	6
12:25227319	donor_gain	1.0000
12:25245397	acceptor_gain	1.0000
12:25250749–25250750	donor_loss	1.0000	3
12:25209854	donor_gain	0.9900
12:25225612	donor_loss	0.9900
12:25227298–25227299	donor_gain	0.9900	2
12:25245272–25245273	donor_loss	0.9900	6

AlphaMissense

753 missense substitutions predicted likely pathogenic (of 1,249 scored), across 136 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M72	9	0.950	0.998
M67	9	0.935	0.999
D57	8	1.000	1.000
D38	8	0.998	1.000
D33	8	0.997	1.000
D119	8	0.996	0.998
D54	8	0.993	0.998
N116	8	0.990	1.000
D69	8	0.989	0.998
F28	8	0.985	1.000
F78	8	0.983	1.000
D47	8	0.971	0.995
S17	8	0.946	0.999
D105	8	0.838	0.966
D92	8	0.804	0.948
F82	7	0.997	0.999
K16	7	0.996	1.000
E37	7	0.991	0.998
R68	7	0.987	0.999
R41	7	0.982	0.998

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	1.57e-06
Lung Adenocarcinoma (TCGA)	unfavorable	0.000346
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	unfavorable	0.000434

Disease associations

OMIM: gene MIM:190070 | disease phenotypes: MIM:211980, MIM:163950, MIM:109800, MIM:607785, MIM:613001, MIM:260350, MIM:613659, MIM:108010, MIM:162900, MIM:163200, MIM:600268, MIM:609942, MIM:614470, MIM:615278, MIM:114480, MIM:601626, MIM:608354, MIM:608355, MIM:608232, MIM:115150, MIM:601518, MIM:188550, MIM:254500, MIM:114500

GenCC curated gene-disease

7 curated gene-disease records:

Disease	Classification	Inheritance	Records
Noonan syndrome 3	Definitive	Autosomal dominant	5
cardiofaciocutaneous syndrome 2	Definitive	Autosomal dominant	5
Noonan syndrome	Definitive	Autosomal dominant	2
cardiofaciocutaneous syndrome	Strong	Autosomal dominant	2
linear nevus sebaceous syndrome	Strong	Autosomal dominant
autoimmune lymphoproliferative syndrome type 4	Strong	Autosomal dominant
Costello syndrome	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

3 validity classifications:

Disease	Classification	Inheritance
cardiofaciocutaneous syndrome	Strong	AD
Noonan syndrome	Definitive	AD
Costello syndrome	Disputed	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (24 panels, 22 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

24 panels:

Panel	Rating
Adult solid tumours cancer susceptibility	green
Childhood solid tumours	green
Childhood solid tumours cancer susceptibility	green
DDG2P	green
Early onset or syndromic epilepsy	green
Embryonal tumour of possible germline origin	green
Fetal anomalies	green
Fetal hydrops	green
Hypotonic infant	green
IUGR and IGF abnormalities	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Monogenic short stature	green
Mosaic skin disorders - Deep sequencing	green
Paediatric disorders	green
Paediatric or syndromic cardiomyopathy	green
Pigmentary skin disorders	green
Primary lymphoedema	green
RASopathies	green
Rare syndromic craniosynostosis or isolated multisuture synostosis	green
Sarcoma of possible germline origin	green
Unexplained death in infancy and sudden unexplained death in childhood	green
COVID-19 research	amber
Primary immunodeficiency or monogenic inflammatory bowel disease	amber

Mondo (45): RASopathy (MONDO:0021060), endometrial carcinoma (MONDO:0002447), lung adenocarcinoma (MONDO:0005061), lung carcinoma (MONDO:0005138), non-small cell lung carcinoma (MONDO:0005233), gallbladder cancer (MONDO:0005411), lung cancer (MONDO:0008903), Noonan syndrome (MONDO:0018997), urinary bladder cancer (MONDO:0001187), squamous cell lung carcinoma (MONDO:0005097), breast adenocarcinoma (MONDO:0004988), juvenile myelomonocytic leukemia (MONDO:0011908), encephalocraniocutaneous lipomatosis (MONDO:0013074), familial pancreatic carcinoma (MONDO:0015278), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), gastric cancer (MONDO:0001056), exocrine pancreatic carcinoma (MONDO:0005192), atypical endometrial hyperplasia (MONDO:0006096), endometrial hyperplasia without atypia (MONDO:0006193), arteriovenous malformations of the brain (MONDO:0007154), nevus, epidermal (MONDO:0008093), linear nevus sebaceous syndrome (MONDO:0008097), Toriello-Lacassie-Droste syndrome (MONDO:0010854), Noonan syndrome 3 (MONDO:0012371), autoimmune lymphoproliferative syndrome type 4 (MONDO:0013767), cardiofaciocutaneous syndrome 2 (MONDO:0014112), hereditary breast carcinoma (MONDO:0016419), acute myeloid leukemia (MONDO:0018874), capillary malformation-arteriovenous malformation 1 (MONDO:0020783), ovarian neoplasm (MONDO:0021068), lung sarcomatoid carcinoma (MONDO:0006279), chronic myeloid leukemia (MONDO:0011996), vascular malformation (MONDO:0024291), cardiofaciocutaneous syndrome (MONDO:0015280), hereditary diffuse gastric adenocarcinoma (MONDO:0007648), Noonan syndrome 1 (MONDO:0008104), pilocytic astrocytoma (MONDO:0016691), prostate cancer, hereditary, 1 (MONDO:0011098), thyroid cancer, nonmedullary, 1 (MONDO:0008567), cardiofaciocutaneous syndrome 1 (MONDO:0007265), plasma cell myeloma (MONDO:0009693), colorectal cancer (MONDO:0005575), pyogenic granuloma (MONDO:0022096), hereditary breast ovarian cancer syndrome (MONDO:0003582), Costello syndrome (MONDO:0009026)

Orphanet (29): RASopathy (Orphanet:536391), Noonan syndrome (Orphanet:648), Familial pancreatic carcinoma (Orphanet:1333), Encephalocraniocutaneous lipomatosis (Orphanet:2396), Juvenile myelomonocytic leukemia (Orphanet:86834), Noonan syndrome and Noonan-related syndrome (Orphanet:98733), Cardiofaciocutaneous syndrome (Orphanet:1340), Capillary malformation-arteriovenous malformation (Orphanet:137667), Rare carcinoma of pancreas (Orphanet:217074), Hereditary breast cancer (Orphanet:227535), Linear nevus sebaceus syndrome (Orphanet:2612), RAS-associated autoimmune leukoproliferative disease (Orphanet:268114), Oculoectodermal syndrome (Orphanet:3339), Brain arteriovenous malformation (Orphanet:46724), Acute myeloid leukemia (Orphanet:519), RASA1-related capillary malformation-arteriovenous malformation (Orphanet:693907), Woolly hair nevus (Orphanet:79414), Chronic myeloid leukemia (Orphanet:521), Hereditary diffuse gastric cancer (Orphanet:26106), Pilocytic astrocytoma (Orphanet:251612), Familial prostate cancer (Orphanet:1331), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145), NON RARE IN EUROPE: Adenocarcinoma of the lung (Orphanet:415268), NON RARE IN EUROPE: Non-small cell lung cancer (Orphanet:488201), NON RARE IN EUROPE: Bladder cancer (Orphanet:157980), Parkes Weber syndrome (Orphanet:90307), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667)

HPO phenotypes

showing 60 of 401 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000014	Abnormality of the bladder
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000036	Abnormal penis morphology
HP:0000039	Epispadias
HP:0000044	Hypogonadotropic hypogonadism
HP:0000047	Hypospadias
HP:0000069	Abnormality of the ureter
HP:0000078	Abnormality of the genital system
HP:0000085	Horseshoe kidney
HP:0000126	Hydronephrosis
HP:0000164	Abnormality of the dentition
HP:0000176	Submucous cleft hard palate
HP:0000179	Thick lower lip vermilion
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000242	Parietal bossing
HP:0000256	Macrocephaly
HP:0000267	Cranial asymmetry
HP:0000268	Dolichocephaly
HP:0000269	Prominent occiput
HP:0000271	Abnormality of the face
HP:0000276	Long face
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000384	Preauricular skin tag
HP:0000391	Thickened helices
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000414	Bulbous nose
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000474	Thickened nuchal skin fold
HP:0000475	Broad neck
HP:0000476	Cystic hygroma
HP:0000478	Abnormality of the eye
HP:0000482	Microcornea
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000488	Retinopathy
HP:0000492	Abnormal eyelid morphology
HP:0000494	Downslanted palpebral fissures
HP:0000499	Abnormal eyelash morphology
HP:0000502	Abnormal conjunctiva morphology

GWAS associations

4 associations:

Study	Trait	p-value
GCST90013407_30	Liver enzyme levels (gamma-glutamyl transferase)	4e-20
GCST90011898_61	Alanine aminotransferase levels	3e-8
GCST003927_3	Dysmenorrheic pain	6e-7
GCST009144_31	Disease progression in age-related macular degeneration (adjusted for baseline)	3e-6

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0007889	dysmenorrheic pain measurement
EFO:0008336	disease progression measurement
EFO:0004532	serum gamma-glutamyl transferase measurement

MeSH disease descriptors

18 disease descriptors:

Descriptor	Name	Tree numbers
D002289	Carcinoma, Non-Small-Cell Lung	C04.588.894.797.520.109.220.249; C08.381.540.140.500; C08.785.520.100.220.500
D056685	Costello Syndrome	C05.660.207.219; C16.131.077.256; C16.320.188
D017789	Granuloma, Pyogenic	C23.550.382.937
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D002538	Intracranial Arteriovenous Malformations	C10.228.140.300.520; C10.500.190.500; C14.240.850.750.295; C14.240.850.875.500; C14.907.150.295; C14.907.253.560.400; C16.131.240.850.750.295; C16.131.240.850.875.500; C16.131.666.190.500
D015470	Leukemia, Myeloid, Acute	C04.557.337.539.275; C15.378.508.539.275
D054429	Leukemia, Myelomonocytic, Juvenile	C04.557.337.539.525; C15.378.190.615.520; C15.378.508.539.525
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690
D054079	Vascular Malformations	C14.240.850; C16.131.240.850
C563969	Aplasia Cutis Congenita with Epibulbar Dermoids *(supp.)*
C562840	Breast Cancer, Familial *(supp.)*
C535579	Cardiofaciocutaneous syndrome *(supp.)*
C535736	Encephalocraniocutaneous lipomatosis *(supp.)*
C580062	Epidermal Nevus *(supp.)*
C537846	Noonan like syndrome *(supp.)*
C537847	Noonan syndrome 3 *(supp.)*
C535837	Pancreatic carcinoma, familial *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (9): CHEMBL2189121 (SINGLE PROTEIN), CHEMBL4523623 (PROTEIN-PROTEIN INTERACTION), CHEMBL4524006 (PROTEIN FAMILY), CHEMBL5169273 (PROTEIN-PROTEIN INTERACTION), CHEMBL5291977 (PROTEIN-PROTEIN INTERACTION), CHEMBL5465393 (PROTEIN COMPLEX), CHEMBL5483196 (PROTEIN-PROTEIN INTERACTION), CHEMBL6193817 (PROTEIN-PROTEIN INTERACTION), CHEMBL6193831 (PROTEIN-PROTEIN INTERACTION)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the KRAS protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

2 curated-mechanism drugs:

Drug	Modality	Max phase
ADAGRASIB	Small molecule	4
SOTORASIB	Small molecule	4

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes KRAS — the drug acts on the assembly or class, not necessarily on this subunit alone.

1 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
SALIRASIB	RAS	3	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 51,679 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

11 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL4594350	ADAGRASIB	4	3,036
CHEMBL4535757	SOTORASIB	4	4,199
CHEMBL2028663	DABRAFENIB	4	13,060
CHEMBL298734	LONAFARNIB	4	13,020
CHEMBL1229517	VEMURAFENIB	4	16,487
CHEMBL5077861	OPNURASIB	3	526
CHEMBL5095236	DIVARASIB	2	683
CHEMBL5314518	GLECIRASIB	2	24
CHEMBL351706	BMS-214662	1	403
CHEMBL3577124	LY-3009120	1	211
CHEMBL4858364	MRTX-1133	1	30

Clinical evidence (CIViC)

Drug × variant × indication, from 387 curated evidence items; also 27 prognostic, 12 oncogenic, 7 diagnostic, 3 functional, 2 predisposing. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

showing 30 of 247 predictive associations by evidence level:

Variant	Therapy	Indication	Effect	Level	CIViC
KRAS G12C	Sotorasib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID9431 +4
KRAS G12C	Adagrasib + Cetuximab	Colorectal Cancer	Sensitivity/Response	CIViC A	EID12063
KRAS G12C	Sotorasib + Panitumumab	Colorectal Cancer	Sensitivity/Response	CIViC A	EID12264
KRAS Mutation	Avutometinib And Defactinib	Ovary Serous Adenocarcinoma	Sensitivity/Response	CIViC A	EID12818
KRAS Wildtype	Chemotherapy + Cetuximab	Colorectal Cancer	Sensitivity/Response	CIViC A	EID11262
KRAS Wildtype	Chemotherapy + Panitumumab	Colorectal Cancer	Sensitivity/Response	CIViC A	EID11264
KRAS Exon 2 Mutation	Cetuximab	Colorectal Cancer	Resistance	CIViC A	EID993 +1
KRAS Mutation	Selumetinib + Docetaxel	Lung Non-small Cell Carcinoma	Resistance	CIViC A	EID2998
KRAS Mutation	Panitumumab + Cetuximab	Colorectal Cancer	Resistance	CIViC A	EID5345
KRAS G13D	Cetuximab	Colorectal Cancer	Sensitivity/Response	CIViC B	EID306 +1
KRAS Mutation	Trametinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID1220 +1
BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1 Inactivating Mutation	Selumetinib	Cancer	Sensitivity/Response	CIViC B	EID11696
BRAF V600E OR NRAS Mutation OR HRAS Mutation OR KRAS Mutation OR NF1 Mutation	Selumetinib	Cancer	Sensitivity/Response	CIViC B	EID11681
KRAS Amplification	Carboplatin + Docetaxel + Sorafenib	Skin Melanoma	Sensitivity/Response	CIViC B	EID1497
KRAS Exon 2 Mutation	Irinotecan + Selumetinib	Colorectal Cancer	Sensitivity/Response	CIViC B	EID1326
KRAS Exon 2 Mutation	Regorafenib Anhydrous	Colorectal Cancer	Sensitivity/Response	CIViC B	EID87
KRAS G12/G13	Trametinib	Pancreatic Adenocarcinoma	Sensitivity/Response	CIViC B	EID990
KRAS G12C	Sotorasib	Solid Tumors, Advanced	Sensitivity/Response	CIViC B	EID10110
KRAS G12C	Docetaxel + Selumetinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID1142
KRAS G12C	Divarasib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID11652
KRAS G12C	Sotorasib	Pancreatic Cancer	Sensitivity/Response	CIViC B	EID11680
KRAS G12C	Adagrasib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID13009
KRAS G12C	Sotorasib	Cancer	Sensitivity/Response	CIViC B	EID8068
KRAS G12D	KRAS G12D Inhibitor HRS-4642	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID12137
KRAS G12D	Setidegrasib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID12937
KRAS G12D	Setidegrasib	Pancreatic Ductal Adenocarcinoma	Sensitivity/Response	CIViC B	EID12938
KRAS G12D	Adebrelimab + KRAS G12D Inhibitor HRS-4642	Pancreatic Ductal Adenocarcinoma	Sensitivity/Response	CIViC B	EID13294
KRAS G12V	Selumetinib + Docetaxel	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID1143
KRAS G13D	Cetuximab + Chemotherapy	Colorectal Adenocarcinoma	Sensitivity/Response	CIViC B	EID11054
KRAS G13D	Cetuximab	Colon Cancer	Sensitivity/Response	CIViC B	EID6974

CIViC column: a representative evidence item (EID); +N = additional CIViC items supporting the same association.

Clinical-actionability assertions (CIViC AMP/ASCO/CAP)

Curated AMP/ASCO/CAP tier assertions — the clinical-actionability classification (Tier I highest) for this gene’s variants, distilling the CIViC evidence above into a tiered call.

8 CIViC assertions:

Molecular profile	Disease	Therapy	Type	AMP tier	Significance
KRAS G12C	Colorectal Cancer	Cetuximab †	Predictive	Tier I - Level A	Resistance
KRAS G12C	Colorectal Cancer	Panitumumab †	Predictive	Tier I - Level A	Resistance
KRAS A146P	Colorectal Cancer	Cetuximab	Predictive	Tier I - Level A	Resistance
KRAS G12A	Cancer		Oncogenic		Oncogenic
KRAS Q61K	Cancer		Oncogenic		Oncogenic
KRAS R164Q (exon 5b)	Cancer		Oncogenic		Uncertain Significance
KRAS A146P	Colorectal Cancer		Oncogenic		Likely Oncogenic
KRAS R164Q (exon 5b)	Cancer		Oncogenic		Likely Benign

† an FDA-approved companion diagnostic exists for this assertion.

CIViC curated variants (29)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

R164Q (exon 5b) (missense variant), G12A (missense variant), G13V (missense variant), Q61 (protein altering variant), RS61764370 (3 prime UTR variant), A146, Wildtype (wild type), A146V (missense variant), G10_A11insG, A11_G12insGA, Mutation (protein altering variant), G12V (missense variant), Q22* (stop gained), G12R (missense variant), Amplification (transcript amplification), Exon 2 Mutation (missense variant), G12 (protein altering variant), G12/G13 (protein altering variant), G12C (missense variant), G12D (missense variant), G13 (missense variant,inframe insertion), G13D (missense variant), A146P (missense variant), A146T (missense variant), Q61H (missense variant), Q61L (missense variant), Q61R (missense variant), Q61K (missense variant), G12S (missense variant).

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

2 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs112445441	Efficacy	3	cetuximab	Colorectal Neoplasms
rs61764370	Efficacy	3	cetuximab;panitumumab	Neoplasms

PharmGKB variants

2 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs61764370	ETFRF1, KRAS	3	2.75	1	cetuximab;panitumumab
rs112445441	KRAS	3	3.12	1	cetuximab

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

7 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs61764370	cetuximab, panitumumab	Efficacy	Genotypes AC + CC is associated with increased progression-free survival when treated with cetuximab or panitumumab in people with Colorectal Neoplasms as compared to genotype AA.	PMID:25183481
rs61764370	capecitabine, cetuximab, oxaliplatin	Efficacy	Genotype AC is associated with increased response to capecitabine, cetuximab and oxaliplatin in people with Rectal Neoplasms as compared to genotype AA.	PMID:26162609
rs112445441	cetuximab, fluorouracil, irinotecan, oxaliplatin	Efficacy	Allele T is associated with increased progression-free survival when treated with cetuximab, fluorouracil, irinotecan and oxaliplatin in people with Colorectal Neoplasms.	PMID:22734028
rs112445441	cetuximab	Efficacy	Allele T is associated with increased overall survival when treated with cetuximab in people with Colorectal Neoplasms.	PMID:20978259
rs112445441	cetuximab, panitumumab	Efficacy	Allele A is associated with increased overall survival when treated with cetuximab or panitumumab in people with Colorectal Neoplasms.	PMID:23090619
rs121913530	ipilimumab, nivolumab, pembrolizumab	Efficacy	Allele A is associated with increased likelihood of Progression-free survival and Overall survival when treated with ipilimumab, nivolumab or pembrolizumab in people with Non-Small Cell Lung Carcinoma as compared to allele C.	PMID:41095904
rs61764370	cetuximab, panitumumab	Efficacy	Allele C is associated with nonresponse to anti-EGFR-based treatment when treated with cetuximab and panitumumab in people with Adenocarcinoma as compared to genotype AA.	PMID:23324806

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — RAS subfamily

Most potent curated ligand interactions (24 total), top 24:

Ligand	Action	Affinity	Parameter
MRTX1133	Inhibition	12.7	pKd
divarasib	Inhibition	12.62	pKd
sotorasib	Inhibition	10.39	pKi
LUNA18	Inhibition	10.37	pKd
elisrasib	Inhibition	10.18	pKi
olomorasib	Inhibition	9.02	pIC50
BI-0474	Inhibition	8.6	pKi
AZD4625	Negative	8.52	pIC50
ERAS-5024	Inhibition	8.41	pIC50
compound 25 [PMID: 32023060]	Inhibition	8.3	pIC50
lonafarnib	Inhibition	8.28	pIC50
sosimerasib	Inhibition	8.05	pIC50
BI-2493	Inhibition	8.0	pKd
QTX3034	Inhibition	8.0	pIC50
opnurasib	Inhibition	7.77	pIC50
garsorasib	Inhibition	7.77	pIC50
compound 15 [PMID: 41769711]	Inhibition	7.77	pIC50
AMG410	Inhibition	7.66	pKd
fulzerasib	Inhibition	7.6	pIC50
ASP2453	Inhibition	7.4	pIC50
compound 39 [PMID: 41770619]	Inhibition	7.1	pIC50
ARS-1620	Inhibition	6.92	pIC50
daraxonrasib	Inhibition	6.44	pKd
adagrasib	Inhibition	5.43	pKi

Binding affinities (BindingDB)

4590 measured of 5364 human assays (6100 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethylnaphthalen-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidine	IC50	0.001 nM	US-20230279025: KRAS G12D INHIBITORS
(2R,6S)-8-[[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(8-ethylnaphthalen-1-yl)-8-fluoropyrido[4,3-d]pyrimidin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizine-2,6-diol	IC50	0.006 nM	US-20230279025: KRAS G12D INHIBITORS
4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-7-(7,8-difluoronaphthalen-1-yl)-8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)pyrido[4,3-d]pyrimidine	IC50	0.007 nM	US-20230279025: KRAS G12D INHIBITORS
4-[2-(1,2,3,5,6,7,8,8a-octahydroindolizin-8-ylmethoxy)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoropyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol	IC50	0.012 nM	US-20230279025: KRAS G12D INHIBITORS
(4R,7S,8R)-14-(8-ethynyl-7-fluoronaphthalen-1-yl)-15-fluoro-18-[[(3S,8S)-3-[[5-(trifluoromethyl)pyridazin-3-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-2,13,17,19,21-pentazapentacyclo[10.7.1.14,7.02,8.016,20]henicosa-1(19),12(20),13,15,17-pentaene	IC50	0.02 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
(4R,7S,8R)-14-(8-ethynyl-7-fluoronaphthalen-1-yl)-15-fluoro-18-[[(3S,8S)-3-[[6-(trifluoromethyl)pyrimidin-4-yl]sulfanylmethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-2,13,17,19,21-pentazapentacyclo[10.7.1.14,7.02,8.016,20]henicosa-1(19),12(20),13,15,17-pentaene	IC50	0.02 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-7-(7-fluoronaphthalen-1-yl)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)pyrido[4,3-d]pyrimidine	IC50	0.027 nM	US-20230279025: KRAS G12D INHIBITORS
5-ethyl-6-fluoro-4-[(4R,7S,8S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]naphthalen-2-ol	KD	0.03 nM	US-20240327434: FUSED TETRACYCLIC COMPOUND, PREPARATION METHOD THEREFOR AND APPLICATION THEREOF IN MEDICINE
(6S,7R)-13-(8-ethynyl-7-fluoronaphthalen-1-yl)-14-fluoro-6-propyl-17-[[(3S,8S)-3-[[5-(trifluoromethyl)pyrazin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-2,5,12,16,18-pentazatetracyclo[9.7.1.02,7.015,19]nonadeca-1(18),11(19),12,14,16-pentaene	IC50	0.04 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
(4R,7S,8R)-18-[[(3S,8S)-3-[[5-(difluoromethyl)pyrimidin-4-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-14-(8-ethynyl-7-fluoronaphthalen-1-yl)-15-fluoro-2,13,17,19,21-pentazapentacyclo[10.7.1.14,7.02,8.016,20]henicosa-1(19),12(20),13,15,17-pentaene	IC50	0.04 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
5-ethynyl-6-fluoro-4-[(4R,7S,8R)-14-fluoro-17-[[1-[(4-fluoropiperidin-1-yl)methyl]cyclopropyl]methoxy]-4-methyl-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]naphthalen-2-ol	IC50	0.05 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
5-ethynyl-6-fluoro-4-[(4R,7S,8S,9S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-9-methyl-2,16,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]naphthalen-2-amine	IC50	0.05 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
(4R,7S,8R)-18-[[(3S,8S)-3-[[5-(difluoromethyl)pyrazin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-14-(8-ethynyl-7-fluoronaphthalen-1-yl)-15-fluoro-2,13,17,19,21-pentazapentacyclo[10.7.1.14,7.02,8.016,20]henicosa-1(19),12(20),13,15,17-pentaene	IC50	0.05 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
3-chloro-2-fluoro-5-[(4R,7S,8S,9S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]-4-(trifluoromethyl)aniline	IC50	0.05 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
5-chloro-4-[(4R,7S,8S,9S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]naphthalen-2-ol	IC50	0.057 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
5-ethynyl-4-[(4R,7S,8S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]naphthalen-2-ol	IC50	0.058 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
5-ethynyl-6-fluoro-4-[(4R,7S,8S,9S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]naphthalen-2-ol	IC50	0.059 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
5-ethynyl-6-fluoro-4-[(4R,7S,8R)-15-fluoro-18-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-2,13,17,19,21-pentazapentacyclo[10.7.1.14,7.02,8.016,20]henicosa-1(19),12(20),13,15,17-pentaen-14-yl]naphthalen-2-ol	IC50	0.06 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
(4R,7S,8R)-18-[[(3S,8S)-3-[[6-(difluoromethyl)pyrimidin-4-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-14-(8-ethynyl-7-fluoronaphthalen-1-yl)-15-fluoro-2,13,17,19,21-pentazapentacyclo[10.7.1.14,7.02,8.016,20]henicosa-1(19),12(20),13,15,17-pentaene	IC50	0.06 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
(4R,7S,8R)-18-[[(3S,8S)-3-[[3-(difluoromethyl)pyrazin-2-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-14-(8-ethynyl-7-fluoronaphthalen-1-yl)-15-fluoro-2,13,17,19,21-pentazapentacyclo[10.7.1.14,7.02,8.016,20]henicosa-1(19),12(20),13,15,17-pentaene	IC50	0.06 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
5-ethyl-4-[(4R,7S,8S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]naphthalen-2-ol	IC50	0.06 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
5-ethynyl-4-[(4R,7S,8S,9S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]naphthalen-2-ol	IC50	0.06 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[2-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]ethoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol	IC50	0.062 nM	US-20230279025: KRAS G12D INHIBITORS
5-ethyl-4-[(4R,7S,8S,9S)-14-fluoro-9-methyl-17-[[(8S)-6-methylidene-2,3,5,7-tetrahydro-1H-pyrrolizin-8-yl]methoxy]-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]naphthalen-2-ol	IC50	0.068 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
(4R,7S,8R,11R)-14-(8-ethynyl-7-fluoronaphthalen-1-yl)-15-fluoro-18-[[(3S,8S)-3-(fluoromethyl)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-11-methyl-2,13,17,19,21-pentazapentacyclo[10.7.1.14,7.02,8.016,20]henicosa-1(19),12,14,16(20),17-pentaene	IC50	0.07 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
(4R,7S,8R)-14-(8-ethynyl-7-fluoronaphthalen-1-yl)-15-fluoro-18-[[(3S,8S)-3-[[6-(trifluoromethyl)pyridazin-4-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-2,13,17,19,21-pentazapentacyclo[10.7.1.14,7.02,8.016,20]henicosa-1(19),12(20),13,15,17-pentaene	IC50	0.07 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
2,3-difluoro-5-[(4R,7S,8S,9S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]-4-(trifluoromethyl)aniline	IC50	0.07 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
3-[(4R,7S,8S,9S)-17-[[(8S)-1’,1’-difluorospiro[2,3,5,7-tetrahydro-1H-pyrrolizine-6,2’-cyclopropane]-8-yl]methoxy]-14-fluoro-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]-5-methyl-4-(trifluoromethyl)aniline	IC50	0.07 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
5-[(4R,7S,8S,9S)-17-[[(3aS)-1-methyl-3,4,6,6a-tetrahydro-2H-furo[3,4-b]pyrrol-3a-yl]methoxy]-14-fluoro-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]-2-fluoro-3-methyl-4-(trifluoromethyl)aniline	IC50	0.07 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
2-fluoro-5-[(4R,7S,8S,9S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]-3-methyl-4-(trifluoromethyl)aniline	IC50	0.074 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
5-ethynyl-6-fluoro-4-[(4R,7S,8R)-14-fluoro-17-[[1-[[(3R)-3-fluoropiperidin-1-yl]methyl]cyclopropyl]methoxy]-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]naphthalen-2-ol	IC50	0.08 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
4-[(4R,7S,8S,9S)-17-[[(5R)-3,3-difluoro-1-azabicyclo[3.2.0]heptan-5-yl]methoxy]-14-fluoro-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]-5-ethynylnaphthalen-2-ol	IC50	0.08 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
(3S,7S,8aR)-3-[[(4R,7S,8S,9S)-13-[5-amino-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl]-14-fluoro-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-17-yl]oxymethyl]-N,N-dimethyl-1,2,3,5,6,7,8,8a-octahydroindolizine-7-carboxamide	IC50	0.08 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
5-[(4R,7S,8S,9S)-17-[[(1R)-2,2-difluoro-1-(2-oxa-6-azaspiro[3.3]heptan-6-ylmethyl)cyclopropyl]methoxy]-14-fluoro-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]-2-fluoro-3-methyl-4-(trifluoromethyl)aniline	IC50	0.08 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
2-fluoro-5-[(4R,7S,8S,9S)-14-fluoro-17-[[1-[(3-fluoroazetidin-1-yl)methyl]cyclopropyl]methoxy]-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]-3-methyl-4-(trifluoromethyl)aniline	IC50	0.08 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
5-ethyl-4-[(4R,7S,8S,9S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]naphthalen-2-ol	IC50	0.082 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
5-[(4R,7S,8S,9S)-17-[[(8S)-1’,1’-difluorospiro[2,3,5,7-tetrahydro-1H-pyrrolizine-6,2’-cyclopropane]-8-yl]methoxy]-14-fluoro-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]-2-fluoro-3-methyl-4-(trifluoromethyl)aniline	IC50	0.083 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
5-ethynyl-6-fluoro-4-[(4R,7S,8S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]naphthalen-2-ol	IC50	0.085 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
2-fluoro-5-[(4R,7S,8S,9S)-14-fluoro-17-[[(3R)-3-fluoro-1-azabicyclo[3.2.0]heptan-5-yl]methoxy]-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]-3-methyl-4-(trifluoromethyl)aniline	IC50	0.086 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
5-[(4R,7S,8S,9S)-17-[[(6S,8aS)-3,4,6,7,8,8a-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-6-yl]methoxy]-14-fluoro-9-methyl-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]-2-fluoro-3-methyl-4-(trifluoromethyl)aniline	IC50	0.087 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
(4R,7S,8R)-18-[[(3S,8S)-3-[[2-(difluoromethyl)pyrimidin-4-yl]oxymethyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-14-(8-ethynyl-7-fluoronaphthalen-1-yl)-15-fluoro-2,13,17,19,21-pentazapentacyclo[10.7.1.14,7.02,8.016,20]henicosa-1(19),12(20),13,15,17-pentaene	IC50	0.09 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
2-fluoro-5-[(4R,7S,8S,9S)-14-fluoro-9-methyl-17-[[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy]-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]-3-methyl-4-(trifluoromethyl)aniline	IC50	0.09 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
2-fluoro-5-[(4R,7S,8S,9S)-14-fluoro-9-methyl-17-[[1-[[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methyl]cyclopropyl]methoxy]-10-oxa-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]-3-methyl-4-(trifluoromethyl)aniline	IC50	0.09 nM	US-20240025919: AZA-TETRACYCLIC OXAZEPINE COMPOUNDS AND USES THEREOF
3-chloro-5-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-4-(trifluoromethyl)phenol	IC50	0.1 nM	US-11453683: KRas G12D inhibitors
5-ethynyl-6-fluoro-4-[(4R,7S,8R)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]naphthalen-2-ol	IC50	0.1 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
5-ethynyl-6-fluoro-4-[(4R,7S,8R)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-2,16,18,20-tetrazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11,13,15(19),16-pentaen-13-yl]naphthalen-2-ol	IC50	0.1 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
5-ethynyl-6-fluoro-4-[(4R,7S,8S,9S)-14-fluoro-17-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-9-methyl-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]naphthalen-2-ol	IC50	0.1 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
5-ethynyl-6-fluoro-4-[(4R,7S,8R)-14-fluoro-17-[[1-[[4-(trifluoromethyl)piperidin-1-yl]methyl]cyclopropyl]methoxy]-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]naphthalen-2-ol	IC50	0.1 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
5-ethynyl-6-fluoro-4-[(4R,7S,8R)-14-fluoro-17-[[1-[[(3R)-3-(trifluoromethyl)pyrrolidin-1-yl]methyl]cyclopropyl]methoxy]-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaen-13-yl]naphthalen-2-ol	IC50	0.1 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
(4R,7S,8R)-14-(8-ethynyl-7-fluoronaphthalen-1-yl)-15-fluoro-18-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-2,13,17,19,21-pentazapentacyclo[10.7.1.14,7.02,8.016,20]henicosa-1(19),12(20),13,15,17-pentaene	IC50	0.1 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS

ChEMBL bioactivities

5085 potent at pChembl≥5 of 5516 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	Kd	0.02	nM	CHEMBL6146469
10.51	Kd	0.031	nM	CHEMBL6149336
10.40	Kd	0.04	nM	CHEMBL6142149
10.30	Kd	0.05	nM	CHEMBL6149922
10.00	IC50	0.1	nM	CHEMBL4855757
10.00	Kd	0.1	nM	CHEMBL5863463
10.00	IC50	0.1	nM	CHEMBL5741049
10.00	Kd	0.1	nM	CHEMBL6142115
9.85	Kd	0.14	nM	CHEMBL5573020
9.80	Kd	0.16	nM	CHEMBL5562993
9.80	Kd	0.16	nM	CHEMBL6146640
9.77	Kd	0.17	nM	CHEMBL5572821
9.74	Kd	0.18	nM	CHEMBL5570195
9.72	Kd	0.19	nM	CHEMBL5569602
9.70	IC50	0.2	nM	CHEMBL4857438
9.67	IC50	0.216	nM	CHEMBL5612044
9.64	Kd	0.23	nM	CHEMBL5575367
9.62	Kd	0.24	nM	CHEMBL6103364
9.61	IC50	0.246	nM	CHEMBL5611970
9.59	Kd	0.26	nM	CHEMBL5576025
9.59	Kd	0.26	nM	CHEMBL6102885
9.52	IC50	0.3	nM	CHEMBL4863339
9.52	Kd	0.3	nM	CHEMBL5892737
9.49	Kd	0.32	nM	CHEMBL5570375
9.43	IC50	0.371	nM	CHEMBL5612889
9.40	IC50	0.4	nM	CHEMBL4859236
9.40	IC50	0.4	nM	CHEMBL4876040
9.40	IC50	0.4	nM	MRTX-1133
9.40	Kd	0.4	nM	CHEMBL5804582
9.40	IC50	0.4	nM	CHEMBL5905084
9.40	IC50	0.4	nM	CHEMBL5776467
9.40	IC50	0.4	nM	CHEMBL5996049
9.39	IC50	0.405	nM	CHEMBL5612083
9.33	Kd	0.47	nM	CHEMBL5565237
9.30	IC50	0.5	nM	CHEMBL4857719
9.30	IC50	0.5	nM	CHEMBL5948638
9.30	IC50	0.5	nM	CHEMBL5856093
9.30	IC50	0.5	nM	CHEMBL5187854
9.30	IC50	0.5	nM	CHEMBL5829922
9.29	IC50	0.51	nM	CHEMBL4855521
9.29	IC50	0.51	nM	CHEMBL4852458
9.25	IC50	0.56	nM	CHEMBL4856277
9.23	IC50	0.589	nM	CHEMBL5613663
9.22	IC50	0.6	nM	CHEMBL4867851
9.22	IC50	0.6	nM	CHEMBL4874297
9.22	IC50	0.6	nM	CHEMBL4876243
9.22	IC50	0.6	nM	CHEMBL5840711
9.22	IC50	0.6	nM	CHEMBL6147321
9.19	Kd	0.64	nM	CHEMBL5572706
9.16	IC50	0.689	nM	CHEMBL5612057

PubChem BioAssay actives

1328 with measured affinity, of 5471 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol	1889615: Binding affinity to KRAS (unknown origin) assessed as dissociation constant	kd	<0.0001	uM
3-[1-[(1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl]-8-(2-cyanoethyl)-6-fluoro-4-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(3-hydroxynaphthalen-1-yl)pyrrolo[3,2-c]quinolin-2-yl]-N,N-dimethylpropanamide	2221331: Binding affinity to KRAS (unknown origin) assessed as dissociation constant by SPR analysis	kd	<0.0001	uM
3-[1-[(1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl]-8-(2-cyanoethyl)-4-[3-(dimethylamino)-3-methylazetidin-1-yl]-6-fluoro-7-(3-hydroxynaphthalen-1-yl)imidazo[4,5-c]quinolin-2-yl]-N,N-dimethylpropanamide	2221331: Binding affinity to KRAS (unknown origin) assessed as dissociation constant by SPR analysis	kd	<0.0001	uM
3-[1-[(1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl]-8-(2-cyanoethyl)-4-[3-(dimethylamino)-3-methylazetidin-1-yl]-6-fluoro-7-(3-hydroxynaphthalen-1-yl)pyrrolo[3,2-c]quinolin-2-yl]-N,N-dimethylpropanamide	2221331: Binding affinity to KRAS (unknown origin) assessed as dissociation constant by SPR analysis	kd	<0.0001	uM
3-[1-[(1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl]-8-(2-cyanoethyl)-4-[3-(dimethylamino)azetidin-1-yl]-6-fluoro-7-(3-hydroxynaphthalen-1-yl)imidazo[4,5-c]quinolin-2-yl]-N,N-dimethylpropanamide	2221331: Binding affinity to KRAS (unknown origin) assessed as dissociation constant by SPR analysis	kd	<0.0001	uM
4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[3-(fluoromethyl)-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol	1785782: Displacement of Cy5-labelled tracer from biotinylated GDP-loaded human recombinant KRAS G12D mutant (1 to 169 residues) measured after 60 mins by TR-FRET assay	ic50	0.0001	uM
(3S,9S,18S,21S,25S,28S,34S)-18-[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,21,22,26,29-octamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	2109755: Binding affinity to biotinylated KRAS G12D mutant (unknown origin) incubated for 120 mins by SPR analysis	kd	0.0001	uM
3-[1-[(1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl]-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-2-[(2-oxopiperidin-1-yl)methyl]pyrrolo[3,2-c]quinolin-8-yl]propanenitrile	2221331: Binding affinity to KRAS (unknown origin) assessed as dissociation constant by SPR analysis	kd	0.0001	uM
3-[1-[(1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl]-8-(2-cyanoethyl)-6-fluoro-7-(3-hydroxynaphthalen-1-yl)-4-[(1R)-1-(1-methylpyrrolidin-2-yl)ethoxy]pyrrolo[3,2-c]quinolin-2-yl]-N,N-dimethylpropanamide	2221331: Binding affinity to KRAS (unknown origin) assessed as dissociation constant by SPR analysis	kd	0.0001	uM
5-chloro-4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol	1785782: Displacement of Cy5-labelled tracer from biotinylated GDP-loaded human recombinant KRAS G12D mutant (1 to 169 residues) measured after 60 mins by TR-FRET assay	ic50	0.0002	uM
(3S,9S,18S,21S,25S,28S,34S)-18-[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-[(1R)-1-hydroxyethyl]-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	2109755: Binding affinity to biotinylated KRAS G12D mutant (unknown origin) incubated for 120 mins by SPR analysis	kd	0.0002	uM
(3S,9S,12S,17S,20S,23S,27S,30S,36S)-27-(azetidine-1-carbonyl)-20-[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-30-cyclopentyl-7,10,17,18,24,28,31-heptamethyl-23-(2-methylpropyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1’-cyclopentane]-2,5,8,11,16,19,22,25,29,32,35-undecone	2109755: Binding affinity to biotinylated KRAS G12D mutant (unknown origin) incubated for 120 mins by SPR analysis	kd	0.0002	uM
(3S,9S,12S,17S,20S,23S,27S,30S,36S)-20-[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-30-cyclopentyl-7,10,17,18,24,28,31-heptamethyl-23-(2-methylpropyl)-27-(morpholine-4-carbonyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1’-cyclopentane]-2,5,8,11,16,19,22,25,29,32,35-undecone	2109755: Binding affinity to biotinylated KRAS G12D mutant (unknown origin) incubated for 120 mins by SPR analysis	kd	0.0002	uM
(3S,9S,12S,17S,20S,23S,27S,30S,36S)-20-[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-30-cyclopentyl-N,N,7,10,17,18,24,28,31-nonamethyl-23-(2-methylpropyl)-2,5,8,11,16,19,22,25,29,32,35-undecaoxospiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1’-cyclopentane]-27-carboxamide	2109755: Binding affinity to biotinylated KRAS G12D mutant (unknown origin) incubated for 120 mins by SPR analysis	kd	0.0002	uM
(3S,9S,18S,21S,25S,28S,34S)-18-[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-(2-hydroxyethyl)-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	2109755: Binding affinity to biotinylated KRAS G12D mutant (unknown origin) incubated for 120 mins by SPR analysis	kd	0.0002	uM
5-ethynyl-6-fluoro-4-[8-fluoro-4-[[(1S,2S)-2-fluorocyclopropyl]-methylamino]-2-[[(8S)-6-methylidene-2,3,5,7-tetrahydro-1H-pyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol	2126472: Inhibition of GDP bound KRAS G12V mutant (unknown origin)	ic50	0.0002	uM
4-[2-[dideuterio-[(6R)-3,3,6-trideuterio-6-fluoro-1,2,5,7-tetrahydropyrrolizin-8-yl]methoxy]-8-fluoro-4-[[(1S,2S)-2-fluorocyclopropyl]-(trideuteriomethyl)amino]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol	2126472: Inhibition of GDP bound KRAS G12V mutant (unknown origin)	ic50	0.0002	uM
[(2R)-2,8-dimethyl-2-[(3E,7E)-4,8,12-trimethyltrideca-3,7,11-trienyl]-3,4-dihydrochromen-6-yl] acetate	2221334: Binding affinity to KRAS G12D mutant (unknown origin) assessed as dissociation constant by SPR analysis	kd	0.0002	uM
3-[1-[(1R,4R,5R)-2-azabicyclo[2.1.1]hexan-5-yl]-2-[3-(azetidin-1-yl)-3-oxopropyl]-6-fluoro-4-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-(7-fluoronaphthalen-1-yl)pyrrolo[3,2-c]quinolin-8-yl]propanenitrile	2221331: Binding affinity to KRAS (unknown origin) assessed as dissociation constant by SPR analysis	kd	0.0002	uM
4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynylnaphthalen-2-ol	1785782: Displacement of Cy5-labelled tracer from biotinylated GDP-loaded human recombinant KRAS G12D mutant (1 to 169 residues) measured after 60 mins by TR-FRET assay	ic50	0.0003	uM
(3S,9S,18S,21S,25S,28S,34S)-18-[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-(2-methoxyethyl)-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	2109755: Binding affinity to biotinylated KRAS G12D mutant (unknown origin) incubated for 120 mins by SPR analysis	kd	0.0003	uM
(3S,9S,18S,21S,25S,28S,34S)-18-[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-21-(2-methylpropyl)-25-(piperidine-1-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	2109755: Binding affinity to biotinylated KRAS G12D mutant (unknown origin) incubated for 120 mins by SPR analysis	kd	0.0003	uM
3-[1-[(1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl]-8-(2-cyanoethyl)-4-ethoxy-6-fluoro-7-(3-hydroxynaphthalen-1-yl)pyrrolo[3,2-c]quinolin-2-yl]-N,N-dimethylpropanamide	2221331: Binding affinity to KRAS (unknown origin) assessed as dissociation constant by SPR analysis	kd	0.0003	uM
5-chloro-4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol	1785782: Displacement of Cy5-labelled tracer from biotinylated GDP-loaded human recombinant KRAS G12D mutant (1 to 169 residues) measured after 60 mins by TR-FRET assay	ic50	0.0004	uM
4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynylnaphthalen-2-ol	1785782: Displacement of Cy5-labelled tracer from biotinylated GDP-loaded human recombinant KRAS G12D mutant (1 to 169 residues) measured after 60 mins by TR-FRET assay	ic50	0.0004	uM
5-ethynyl-6-fluoro-4-[8-fluoro-4-[[(1S,2S)-2-fluorocyclopropyl]-methylamino]-2-[(6-methylidene-2,3,5,7-tetrahydro-1H-pyrrolizin-8-yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol;2,2,2-trifluoroacetic acid	2126472: Inhibition of GDP bound KRAS G12V mutant (unknown origin)	ic50	0.0004	uM
5-ethynyl-6-fluoro-4-[8-fluoro-4-[[(1S,2S)-2-fluorocyclopropyl]-methylamino]-2-[(6-methylidene-2,3,5,7-tetrahydro-1H-pyrrolizin-8-yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol;2,2,2-trifluoroethanol	2126472: Inhibition of GDP bound KRAS G12V mutant (unknown origin)	ic50	0.0004	uM
5-chloro-4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)pyrido[4,3-d]pyrimidin-7-yl]-6-fluoronaphthalen-2-ol	1785782: Displacement of Cy5-labelled tracer from biotinylated GDP-loaded human recombinant KRAS G12D mutant (1 to 169 residues) measured after 60 mins by TR-FRET assay	ic50	0.0005	uM
19-chloro-22-[(2S,5R)-2,5-dimethyl-4-prop-2-enoylpiperazin-1-yl]-15,16-difluoro-3-propan-2-yl-11-oxa-1,4,6,23,26-pentazapentacyclo[16.6.2.02,7.012,17.021,25]hexacosa-2(7),3,5,12(17),13,15,18,20,22,25-decaen-24-one	1766135: Inhibition of biotinylated KRAS G12C/C51S/C80L/C118S mutant (unknown origin) pretreated for 60 mins followed by recombinant SOS addition by SOS-catalyzed nucleotide exchange-based TR-FRET analysis	ic50	0.0005	uM
19-chloro-9,9,10,10-tetradeuterio-22-[(2S,5R)-2,5-dimethyl-4-prop-2-enoylpiperazin-1-yl]-15,16-difluoro-3-propan-2-yl-8,11-dioxa-1,4,23,26-tetrazapentacyclo[16.6.2.02,7.012,17.021,25]hexacosa-2(7),3,5,12(17),13,15,18,20,22,25-decaen-24-one	1766135: Inhibition of biotinylated KRAS G12C/C51S/C80L/C118S mutant (unknown origin) pretreated for 60 mins followed by recombinant SOS addition by SOS-catalyzed nucleotide exchange-based TR-FRET analysis	ic50	0.0005	uM
(3S,9S,12S,17S,20S,23S,27S,30S,36S)-20-[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-9-(cyclohexylmethyl)-30-cyclopentyl-7,10,17,18,24,28,31-heptamethyl-23-(2-methylpropyl)-27-(piperidine-1-carbonyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1’-cyclopentane]-2,5,8,11,16,19,22,25,29,32,35-undecone	2109755: Binding affinity to biotinylated KRAS G12D mutant (unknown origin) incubated for 120 mins by SPR analysis	kd	0.0005	uM
4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5,6-difluoronaphthalen-2-ol	1785782: Displacement of Cy5-labelled tracer from biotinylated GDP-loaded human recombinant KRAS G12D mutant (1 to 169 residues) measured after 60 mins by TR-FRET assay	ic50	0.0006	uM
4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol	1785782: Displacement of Cy5-labelled tracer from biotinylated GDP-loaded human recombinant KRAS G12D mutant (1 to 169 residues) measured after 60 mins by TR-FRET assay	ic50	0.0006	uM
4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[(2-methoxy-1,2,3,5,6,7-hexahydropyrrolizin-8-yl)methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-fluoronaphthalen-2-ol	1785782: Displacement of Cy5-labelled tracer from biotinylated GDP-loaded human recombinant KRAS G12D mutant (1 to 169 residues) measured after 60 mins by TR-FRET assay	ic50	0.0006	uM
20-chloro-10,10,17-trifluoro-23-[(2S)-2-methyl-4-prop-2-enoylpiperazin-1-yl]-3-propan-2-yl-12-oxa-1,4,24,27-tetrazapentacyclo[17.6.2.02,7.013,18.022,26]heptacosa-2(7),3,5,13(18),14,16,19,21,23,26-decaen-25-one	1766135: Inhibition of biotinylated KRAS G12C/C51S/C80L/C118S mutant (unknown origin) pretreated for 60 mins followed by recombinant SOS addition by SOS-catalyzed nucleotide exchange-based TR-FRET analysis	ic50	0.0006	uM
177377162	2109755: Binding affinity to biotinylated KRAS G12D mutant (unknown origin) incubated for 120 mins by SPR analysis	kd	0.0006	uM
5-ethynyl-6-fluoro-4-[8-fluoro-4-[[(1S,2S)-2-fluorocyclopropyl]-methylamino]-2-[[(8R)-6-methylidene-2,3,5,7-tetrahydro-1H-pyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol	2126472: Inhibition of GDP bound KRAS G12V mutant (unknown origin)	ic50	0.0006	uM
4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[1-(morpholin-4-ylmethyl)cyclopropyl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-5-iodonaphthalen-2-ol	1777608: Inhibition of recombinant his-tagged KRAS G12D mutant (unknown origin) expressed in Escherichia coli BL21(DE3) assessed as inhibition of GDP-GTP exchange rate in presence of recombinant SOS1/GMPPNP incubated for 1 hr by BODIPY fluorescence assay	ic50	0.0007	uM
4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[1-[(dimethylamino)methyl]cyclopropyl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-5-iodonaphthalen-2-ol	1777608: Inhibition of recombinant his-tagged KRAS G12D mutant (unknown origin) expressed in Escherichia coli BL21(DE3) assessed as inhibition of GDP-GTP exchange rate in presence of recombinant SOS1/GMPPNP incubated for 1 hr by BODIPY fluorescence assay	ic50	0.0007	uM
4-[2-[dideuterio-[(6S)-3,3,6-trideuterio-6-fluoro-1,2,5,7-tetrahydropyrrolizin-8-yl]methoxy]-8-fluoro-4-[[(1S,2S)-2-fluorocyclopropyl]-(trideuteriomethyl)amino]pyrido[4,3-d]pyrimidin-7-yl]-5-ethynyl-6-fluoronaphthalen-2-ol	2126472: Inhibition of GDP bound KRAS G12V mutant (unknown origin)	ic50	0.0007	uM
4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-7-yl]-5-ethyl-6-fluoronaphthalen-2-ol	1785782: Displacement of Cy5-labelled tracer from biotinylated GDP-loaded human recombinant KRAS G12D mutant (1 to 169 residues) measured after 60 mins by TR-FRET assay	ic50	0.0008	uM
(3S,9S,18S,21S,25S,28S,34S)-18-[(2S)-butan-2-yl]-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-25-(piperidine-1-carbonyl)-21-propylspiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclopentane]-2,5,8,11,14,17,20,23,27,30,33-undecone	2109755: Binding affinity to biotinylated KRAS G12D mutant (unknown origin) incubated for 120 mins by SPR analysis	kd	0.0008	uM
3-[1-[(1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl]-6-fluoro-7-(7-fluoronaphthalen-1-yl)-2-[(3-oxomorpholin-4-yl)methyl]-4-(1,2,4-triazol-1-yl)pyrrolo[3,2-c]quinolin-8-yl]propanenitrile	2221331: Binding affinity to KRAS (unknown origin) assessed as dissociation constant by SPR analysis	kd	0.0008	uM
7-(5-chloro-6-methyl-1H-indazol-4-yl)-4-[(3S)-3-(cyanomethyl)-4-prop-2-enoylpiperazin-1-yl]-N-[(2R)-1-(dimethylamino)propan-2-yl]-6,8-dihydro-5H-1,7-naphthyridine-2-carboxamide	1752332: Inhibition of biotinylated KRAS G12C mutant (unknown origin) assessed as inhibition of SOS-catalyzed nucleotide exchange preincubated for 60 mins followed by addition of human recombinant SOS protein and unlabeled GTP and measured after 60 mins by TR-FRET analysis	ic50	0.0009	uM
20-chloro-23-[(2S,5R)-2,5-dimethyl-4-prop-2-enoylpiperazin-1-yl]-10,10,17-trifluoro-3-propan-2-yl-8,12-dioxa-1,4,24,27-tetrazapentacyclo[17.6.2.02,7.013,18.022,26]heptacosa-2(7),3,5,13(18),14,16,19,21,23,26-decaen-25-one	1766135: Inhibition of biotinylated KRAS G12C/C51S/C80L/C118S mutant (unknown origin) pretreated for 60 mins followed by recombinant SOS addition by SOS-catalyzed nucleotide exchange-based TR-FRET analysis	ic50	0.0009	uM
4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[1-[[(3R)-3-fluoropyrrolidin-1-yl]methyl]cyclopropyl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-7-yl]-5-iodonaphthalen-2-ol	1777608: Inhibition of recombinant his-tagged KRAS G12D mutant (unknown origin) expressed in Escherichia coli BL21(DE3) assessed as inhibition of GDP-GTP exchange rate in presence of recombinant SOS1/GMPPNP incubated for 1 hr by BODIPY fluorescence assay	ic50	0.0009	uM
2-amino-4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]-7-fluoro-1-benzothiophene-3-carbonitrile	2020248: Inhibition of GDP-bound biotinylated-KRAS G12D mutant (1 to 169 residues) (unknown origin) assessed as suppression of SOS1-mediated nucleotide exchange by measuring reduction in KRAS G12D mutant-RAF RBD complex formation preincubated for 60 mins followed by SOS1 addition and further incubated for 60 mins and subsequent addition of KRAS G12D mutant-RAF RBD mixture measured after 30 to 60 mins by FRET assay	ic50	0.0009	uM
3-[1-[(1R,4R,5S)-2-azabicyclo[2.1.1]hexan-5-yl]-6-fluoro-7-(7-fluoronaphthalen-1-yl)-4-(2-methyl-4-pyridinyl)-2-[(1R)-1-(3-oxomorpholin-4-yl)ethyl]pyrrolo[3,2-c]quinolin-8-yl]propanenitrile	2221331: Binding affinity to KRAS (unknown origin) assessed as dissociation constant by SPR analysis	kd	0.0009	uM
2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoylpiperazin-2-yl]acetonitrile	1652101: Inhibition of KRAS G12C mutant in human NCI-H358 cells assessed as reduction in ERK phosphorylation incubated for 3 hrs by in-cell western method	ic50	0.0010	uM
2-[(2S)-4-[7-(8-methylnaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-prop-2-enoylpiperazin-2-yl]acetonitrile	1652101: Inhibition of KRAS G12C mutant in human NCI-H358 cells assessed as reduction in ERK phosphorylation incubated for 3 hrs by in-cell western method	ic50	0.0010	uM

CTD chemical–gene interactions

136 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Vinyl Chloride	increases reaction, increases mutagenesis, affects mutagenesis	7
Resveratrol	affects cotreatment, increases expression, decreases expression	5
Tobacco Smoke Pollution	increases mutagenesis, affects expression, increases expression	5
bisphenol A	affects cotreatment, increases expression, decreases expression, increases mutagenesis	4
Quercetin	decreases reaction, decreases expression, affects cotreatment, increases expression, affects activity	4
Tetrachlorodibenzodioxin	decreases reaction, increases expression, affects expression	4
Cadmium Chloride	increases expression, decreases expression, decreases reaction, increases reaction, increases secretion	4
sodium arsenite	affects expression, increases expression	3
Fluorouracil	decreases expression, increases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	3
arsenite	increases expression, increases mutagenesis, decreases reaction	2
hydroquinone	affects expression, increases expression, affects response to substance	2
mercuric bromide	affects cotreatment, decreases expression	2
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases reaction, increases response to substance	2
Gefitinib	affects reaction, affects response to substance, decreases response to substance	2
Arsenic	affects response to substance, increases mutagenesis, affects reaction, increases phosphorylation, increases secretion	2
Cadmium	increases expression, decreases expression	2
Doxorubicin	decreases expression, increases expression	2
Estradiol	decreases expression, increases expression	2
Smoke	affects response to substance, increases mutagenesis	2
Genistein	decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
AZ-628	increases response to substance, affects cotreatment, affects response to substance	1
2-methoxy-6-undecyl-1,4-benzoquinone	decreases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects expression, affects cotreatment	1
ARS-1620	affects binding	1
sotorasib	affects reaction, decreases phosphorylation, increases response to substance, affects binding	1
BI-2852	affects binding, decreases reaction	1
daraxonrasib	decreases activity	1

ChEMBL screening assays

861 unique, capped per target: 829 binding, 32 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2089529	Binding	Binding affinity to K-Ras G12D mutant-GDP complex	Ras inhibition via direct Ras binding–is there a path forward? — *Bioorg Med Chem Lett*
CHEMBL4612363	Functional	In-vivo target engagement at KRAS G12C mutant in athymic nude-Foxn1nu mouse xenografted with human NCI-H358 cells assessed as KRAS G12C modification level in tumor lysate at 10 mg/kg, po dosed via gavage as single administration measured af	Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C Inhibitor for the Treatment of Cancer. — *J Med Chem*

Cellosaurus cell lines

5,637 cell lines: 5,583 cancer cell line, 22 spontaneously immortalized cell line, 12 induced pluripotent stem cell, 7 transformed cell line, 6 hybrid cell line, 4 telomerase immortalized cell line, 2 factor-dependent cell line, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0005	NB4	Cancer cell line	Female
CVCL_0014	RPMI-8226	Cancer cell line	Male
CVCL_0023	A-549	Cancer cell line	Male
CVCL_0026	Capan-2	Cancer cell line	Male
CVCL_0062	MDA-MB-231	Cancer cell line	Female
CVCL_0098	SKM-1	Cancer cell line	Male
CVCL_0099	SNU-1	Cancer cell line	Male
CVCL_0101	SNU-601	Cancer cell line	Male
CVCL_0138	ACH-2	Cancer cell line	Female
CVCL_0139	AGS	Cancer cell line	Female

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 326 trials:

NCT	Phase	Status	Title
NCT04320316	Phase 4	COMPLETED	A Trial to Assess the Safety and Efficacy of KRN23 in Epidermal Nevus Syndrome (ENS)
NCT00365508	Phase 4	COMPLETED	Counseling and Nicotine Replacement Therapy in Helping Adult Smokers Quit Smoking
NCT00558155	Phase 4	COMPLETED	The Impact of Immunostimulating Nutrition on the Outcome of Surgery
NCT00576940	Phase 4	COMPLETED	Standard and Immunostimulating Enteral Nutrition in Surgical Patients
NCT00666978	Phase 4	COMPLETED	Health Education Counseling With or Without Bupropion in Helping African Americans Stop Smoking
NCT01038154	Phase 4	UNKNOWN	Study to Evaluate the Efficacy of Pravastatin on Survival and Recurrence of Advanced Gastroesophageal Cancer
NCT01234272	Phase 4	COMPLETED	Comparison of the Analgesic Effect Between Intrathecal Morphine and IV-fentanyl Patient Controlled Analgesia (ITM-IVPCA) and Epidural PCA (PCEA) in Patients Undergoing Gastrectomy -Randomized Allocation Study-
NCT01260194	Phase 4	TERMINATED	A Study of Herceptin (Trastuzumab) in Combination With Standard Chemotherapy in Patients With HER Positive Metastatic Gastric Cancer
NCT01271582	Phase 4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01401075	Phase 4	COMPLETED	RCT With Adjuvant Mistletoe Treatment in Gastric Cancer Patients
NCT01471756	Phase 4	COMPLETED	Improving Complete Endoscopic Mucosal Resection (EMR) of Colorectal Neoplasia
NCT01766765	Phase 4	UNKNOWN	Early Jejunostomy Nutrition Minimizes Time to Chemotherapy
NCT01910948	Phase 4	UNKNOWN	Perioperative Application of Omega-3 Polyunsaturated Fatty Acids in Gastric Cancer Patients
NCT01927328	Phase 4	UNKNOWN	Iron Replacement in Oesophagogastric Neoplasia
NCT01962272	Phase 4	COMPLETED	The Effect of Nutritional Counseling for Cancer Patients
NCT01962376	Phase 4	UNKNOWN	Preoperative Chemotherapy With Bevacizumab For Potentially Resectable Gastric Cancer With Liver Metastasis
NCT02047994	Phase 4	RECRUITING	Multicentric Randomized Study of H. Pylori Eradication and Pepsinogen Testing for Prevention of Gastric Cancer Mortality
NCT02235246	Phase 4	COMPLETED	The Effect of Perioperative Intravenous Magnesium on Pain After Endoscopic Submucosal Dissection for Gastric Neoplasm: Prospective Randomized Double-blind Placebo Controlled Study
NCT02366819	Phase 4	SUSPENDED	Genetic Analysis-Guided Irinotecan Hydrochloride Dosing of mFOLFIRINOX in Treating Patients With Locally Advanced Gastroesophageal or Stomach Cancer
NCT02401971	Phase 4	UNKNOWN	Irinotecan Plus Thalidomide in Second Line Advanced Gastric Cancer
NCT02458573	Phase 4	COMPLETED	Comparison of the Effects of Continuous Epidural Analgesia and Continuous Intravenous Analgesia on Postoperative Bowel Movement in Patients Undergoing Laparoscopic Gastrectomy
NCT02638584	Phase 4	COMPLETED	Effects of Ilaprazole on Ulcer Healing Rate and Prevention of Gastrointestinal Bleeding in the Patients Undergone ESD.
NCT02776527	Phase 4	UNKNOWN	A Clinical Trial of Maintenance Treatment of Apatinib in Advanced Gastric Cancer Patients Have Completed Postoprative Adjuvant Chemotherapy
NCT03384511	Phase 4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03550482	Phase 4	COMPLETED	Oncoxin® and Quality of Life in Cancer Patients
NCT03609892	Phase 4	COMPLETED	Helicobacter Rescue Therapy With Berberine Plus Amoxicillin Quadruple Therapy Versus Tetracycline Plus Furazolidone Quadruple Therapy
NCT03642093	Phase 4	UNKNOWN	HOPE - A Study to Evaluate the Effect of a Prehabilitation Program on GI Cancer Patients Planning to Undergo Surgery
NCT03733639	Phase 4	UNKNOWN	Tisseel® as a Reinforcement of Esophagojejunal Anastomoses
NCT04168346	Phase 4	NOT_YET_RECRUITING	Preoperative Intravenous Iron Therapy in Patients With Gastric Cancer
NCT04209933	Phase 4	COMPLETED	Helicobacter Pylori Eradication With Different Bismuth Quadruple Therapies
NCT04591028	Phase 4	WITHDRAWN	A Study to Evaluate Indocyanine Green Lymphangiography to Improve Lymphadenectomy in Gastric Cancer Patients
NCT04607057	Phase 4	UNKNOWN	Supplemental Parenteral Nutrition During Postgastrectomy in Nutritionally at Risk Patient
NCT04660123	Phase 4	COMPLETED	A Real World Study of Bismuth Colloidal Pectin Granules Quadruple Therapy for H. Pylori Eradication
NCT04678492	Phase 4	COMPLETED	Helicobacter Rescue Therapy With High-dose Esomeprazole and Amoxicillin Dual Therapy Versus Bismuth-containing Quadruple Therapy
NCT04697186	Phase 4	COMPLETED	Helicobacter Pylori Eradication With Berberine Plus Amoxicillin Triple Therapy Versus Bismuth-containing Quadruple Therapy
NCT05029453	Phase 4	UNKNOWN	Apatinib Combined With Chemotherapy Versus Chemotherapy in Second-line Gastric Cancer Receiving Prior Anti-PD-1 Therapy
NCT05183126	Phase 4	RECRUITING	Pharmacokinetic Study of Skeletal Muscle Area-based Paclitaxel Infusion in Patients With Cancer
NCT05354856	Phase 4	TERMINATED	The Effect of Chemoradiotherapy on Gastric Perfusion in Patients With Gastric Cancer.
NCT05410535	Phase 4	COMPLETED	To Evaluate Efficacy of Ursodeoxycholic Acid (UDCA) for the Prevention of Gallstone Formation After Gasterectomy
NCT05498766	Phase 4	NOT_YET_RECRUITING	Effect and Safety of Huaier Granule Versus SOX Regimen in Gastric Cancer Patients
NCT05518929	Phase 4	COMPLETED	Hypoxia During Gastroenterological Endoscope Procedures Sedated With Ciprofol In Overweight Or Obesity Patients
NCT05688020	Phase 4	UNKNOWN	Tranexamic Acid During Upper GI Endoscopic Resection Procedures
NCT05742568	Phase 4	COMPLETED	Effects of High-dose Dual Therapy and Bismuth Quadruple Therapy for Helicobacter Pylori Eradication on Intestinal Microecology
NCT06169410	Phase 4	UNKNOWN	Ramucirumab Combined With Nab-paclitaxel, Lobaplatin, and S-1 in Neoadjuvant Transformation Therapy for Advanced Gastric Cancer
NCT06499610	Phase 4	NOT_YET_RECRUITING	Clinical Study of Irinotecan Liposome Combination Therapy for Advanced Gastric Cancer
NCT07124351	Phase 4	RECRUITING	Intraoperative Imaging of Gastrointestinal Malignancies Using Pafolacianine (CYTALUX™)
NCT07139366	Phase 4	RECRUITING	Saccharomyces Boulardii Combined With Bismuth Quadruple Therapy for Helicobacter Pylori Rescue Treatment
NCT07224035	Phase 4	ACTIVE_NOT_RECRUITING	Helicobacter Pylori Screening and Treatment in the At-risk South Florida Community- AIM 1
NCT07224048	Phase 4	ACTIVE_NOT_RECRUITING	Helicobacter Pylori Screening and Treatment in the At-risk South Florida Community-AIM 2
NCT07312370	Phase 4	NOT_YET_RECRUITING	Esomeprazole Plus Sucralfate for Post-ESD Ulcer Healing
NCT07467174	Phase 4	NOT_YET_RECRUITING	RCT Comparing Reduced-port Robotic and Conventional Laparoscopic Subtotal Gastrectomy
NCT07502027	Phase 4	NOT_YET_RECRUITING	A Clinical Study of Iparomlimab and Tuvonralimab Combined With SOX Following Heterogeneous Radiotherapy as First-line Treatment for Unresectable Locally Advanced or Metastatic HER2-negative Gastric or Gastroesophageal Junction Adenocarcinoma
NCT07772453	Phase 4	NOT_YET_RECRUITING	Ferric Carboxymaltose Versus Iron Sucrose for Iron Deficiency Anemia After Radical Gastrectomy for Gastric Cancer
NCT07801027	Phase 4	NOT_YET_RECRUITING	A Trial of Pembrolizumab With Chemotherapy or Chemoradiotherapy in Participants From India With Different Types of Cancer (MK-3475-G44/KEYNOTE-G44)
NCT00452725	Phase 3	COMPLETED	Effect of MAXOMAT ® on the Growth of Small Children to NOONAN’s Syndrome
NCT01529840	Phase 3	COMPLETED	Somatropin Effect on Linear Growth and Final Height in Subjects With Noonan Syndrome
NCT01529944	Phase 3	COMPLETED	Genetic Testing of Noonan Subjects Previously Treated With Norditropin®. An Extension to Trial GHNOO-1658
NCT01927861	Phase 3	COMPLETED	Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome
NCT02713945	Phase 3	COMPLETED	Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
NCT05723835	Phase 3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for KRAS across ~30M SureChEMBL compounds — explore on Sugi Predict.