KRAS

Summary

KRAS (KRAS proto-oncogene, GTPase, HGNC:6407) is a protein-coding gene on chromosome 12p12.1, encoding GTPase KRas (P01116). Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. In precision oncology, KRAS G12C confers sensitivity to Sotorasib in Lung Non-small Cell Carcinoma (CIViC Level A); 237 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): 549 total — 39 pathogenic, 39 likely-pathogenic
• Phenotypes (HPO): 372
• Druggable target: yes — 11 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 238 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 36 cancer types
• Cancer dependency (DepMap): dependent in 52.4% of screened cell lines
• MANE Select transcript: NM_004985

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: 16 — 11 protein_coding, 4 nonsense_mediated_decay, 1 retained_intron

ENST00000256078, ENST00000311936, ENST00000556131, ENST00000557334, ENST00000685328, ENST00000686877, ENST00000686969, ENST00000687356, ENST00000688228, ENST00000688940, ENST00000690406, ENST00000690804, ENST00000692768, ENST00000693229, ENST00000894155, ENST00000940422

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.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130178	20.4655	1786

Top tissues by expression

298 total, 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

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

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)

327 targeting KRAS, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

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

DepMap (CRISPR cell-line fitness): dependent in 52.4% of screened cell lines.

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)

Protein

Protein identifiers

GTPase KRas — P01116 (reviewed: P01116)

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

All UniProt accessions (10): A0A8I5KQ21, A0A8I5KQU3, A0A8I5KR86, A0A8I5KUB5, A0A8I5KXN3, A0A8I5KYH6, P01116, G3V4K2, G3V5T7, L7RSL8

UniProt curated annotations — full annotation on UniProt →

Function. Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. Plays an important role in the regulation of cell proliferation. 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.

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 with GPR31; in a farnelysation-dependent manner.

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

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), 1 shown:

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

UniProt features (85 total): sequence variant 34, strand 12, helix 8, mutagenesis site 6, lipid moiety-binding region 5, modified residue 4, binding site 4, chain 2, splice variant 2, turn 2, initiator methionine 1, glycosylation site 1, cross-link 1, propeptide 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

511 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9IAY	X-RAY DIFFRACTION	0.95
9IAW	X-RAY DIFFRACTION	1
8ONV	X-RAY DIFFRACTION	1.01
6P0Z	X-RAY DIFFRACTION	1.01
9IB5	X-RAY DIFFRACTION	1.01
8AZZ	X-RAY DIFFRACTION	1.02
8AZX	X-RAY DIFFRACTION	1.04
8B00	X-RAY DIFFRACTION	1.04
8TVK	X-RAY DIFFRACTION	1.04
4QL3	X-RAY DIFFRACTION	1.04
8AZV	X-RAY DIFFRACTION	1.05
9IB4	X-RAY DIFFRACTION	1.06
9E3S	X-RAY DIFFRACTION	1.08
8AZY	X-RAY DIFFRACTION	1.09
8B78	X-RAY DIFFRACTION	1.11
9N44	X-RAY DIFFRACTION	1.11
8AFB	X-RAY DIFFRACTION	1.12
8FMI	X-RAY DIFFRACTION	1.12
4TQA	X-RAY DIFFRACTION	1.13
9BG4	X-RAY DIFFRACTION	1.14
9G4B	X-RAY DIFFRACTION	1.14
4LDJ	X-RAY DIFFRACTION	1.15
6TAN	X-RAY DIFFRACTION	1.16
8R7W	X-RAY DIFFRACTION	1.16
7O70	X-RAY DIFFRACTION	1.18
8EDY	X-RAY DIFFRACTION	1.18
8EER	X-RAY DIFFRACTION	1.18
9E9I	X-RAY DIFFRACTION	1.18
9IAP	X-RAY DIFFRACTION	1.18
9GGV	X-RAY DIFFRACTION	1.19

Predicted structure (AlphaFold)

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

Antibody-complex structures (SAbDab): 11 — 7MDP, 7RP2, 7RP3, 7STF, 7YV1, 8BE5, 8UDR, 8VR9, 8VRA, 8VRB, 9I5E

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 (4): 10–18; 29–35; 59–60; 116–119

Post-translational modifications (10): 1, 2, 104, 186, 180, 182, 184, 185, 186, 170

Glycosylation sites (1): 35

Mutagenesis-validated functional residues (6):

Position	Phenotype
38	decreased interaction with mapkap1/sin1.
40	decreased interaction with mapkap1/sin1.
61	promotes gtp binding.
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

71 pathways

ID	Pathway
R-HSA-6802946	Signaling by moderate kinase activity BRAF mutants
R-HSA-6802955	Paradoxical activation of RAF signaling by kinase inactive BRAF
R-HSA-8951936	RUNX3 regulates p14-ARF
R-HSA-9648002	RAS processing
R-HSA-9649948	Signaling downstream of RAS mutants
R-HSA-9674555	Signaling by CSF3 (G-CSF)
R-HSA-9680350	Signaling by CSF1 (M-CSF) in myeloid cells
R-HSA-9753510	Signaling by RAS GAP mutants
R-HSA-9753512	Signaling by RAS GTPase mutants
R-HSA-112412	SOS-mediated signalling
R-HSA-1169092	Activation of RAS in B cells
R-HSA-1236382	Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants
R-HSA-1250196	SHC1 events in ERBB2 signaling
R-HSA-1250347	SHC1 events in ERBB4 signaling
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-167044	Signalling to RAS
R-HSA-171007	p38MAPK events
R-HSA-179812	GRB2 events in EGFR signaling
R-HSA-180336	SHC1 events in EGFR signaling
R-HSA-186763	Downstream signal transduction
R-HSA-1963640	GRB2 events in ERBB2 signaling
R-HSA-210993	Tie2 Signaling
R-HSA-2179392	EGFR Transactivation by Gastrin
R-HSA-2424491	DAP12 signaling
R-HSA-2428933	SHC-related events triggered by IGF1R
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-375165	NCAM signaling for neurite out-growth
R-HSA-4086398	Ca2+ pathway
R-HSA-442982	Ras activation upon Ca2+ influx through NMDA receptor
R-HSA-5218921	VEGFR2 mediated cell proliferation

MSigDB gene sets: 0 (showing top):

GO Biological Process (33): MAPK cascade (GO:0000165), liver development (GO:0001889), Ras protein signal transduction (GO:0007265), female pregnancy (GO:0007565), visual learning (GO:0008542), response to gravity (GO:0009629), gene expression (GO:0010467), positive regulation of gene expression (GO:0010628), glial cell proliferation (GO:0014009), Rac protein signal transduction (GO:0016601), cytokine-mediated signaling pathway (GO:0019221), forebrain astrocyte development (GO:0021897), actin cytoskeleton organization (GO:0030036), negative regulation of epithelial cell differentiation (GO:0030857), regulation of synaptic transmission, GABAergic (GO:0032228), positive regulation of Rac protein signal transduction (GO:0035022), response to isolation stress (GO:0035900), skeletal muscle cell differentiation (GO:0035914), negative regulation of neuron apoptotic process (GO:0043524), regulation of long-term neuronal synaptic plasticity (GO:0048169), homeostasis of number of cells within a tissue (GO:0048873), striated muscle cell differentiation (GO:0051146), response to glucocorticoid (GO:0051384), response to mineralocorticoid (GO:0051385), neuron apoptotic process (GO:0051402), myoblast proliferation (GO:0051450), cardiac muscle cell proliferation (GO:0060038), positive regulation of glial cell proliferation (GO:0060252), epithelial tube branching involved in lung morphogenesis (GO:0060441), type I pneumocyte differentiation (GO:0060509), positive regulation of cellular senescence (GO:2000774), signal transduction (GO:0007165), cell population proliferation (GO:0008283)

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

Rollup of top-16 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
guanyl ribonucleotide binding	3
small GTPase-mediated signal transduction	2
anion binding	2
binding	2
plasma membrane	2
intracellular signaling cassette	1
gland development	1
hepaticobiliary system development	1
multi-organism reproductive process	1
multi-multicellular organism process	1
visual behavior	1
associative learning	1
response to abiotic stimulus	1
macromolecule biosynthetic process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
cell population proliferation	1
gliogenesis	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
astrocyte development	1
forebrain astrocyte differentiation	1
cytoskeleton organization	1
actin filament-based process	1
epithelial cell differentiation	1
regulation of epithelial cell differentiation	1
negative regulation of cell differentiation	1
modulation of chemical synaptic transmission	1
synaptic transmission, GABAergic	1
Rac protein signal transduction	1
regulation of Rac protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
multicellular organismal response to stress	1
skeletal muscle tissue development	1
cell differentiation	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1

Protein interactions and networks

STRING

10098 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KRAS	CALML5	Q9NZT1	984
KRAS	CALML3	P27482	983
KRAS	CALML6	Q8TD86	982
KRAS	CALML4	Q96GE6	982
KRAS	RALGDS	Q12967	981
KRAS	CALM1	P02593	978
KRAS	RAF1	P04049	976
KRAS	BRAF	P15056	974
KRAS	SOS1	Q07889	966
KRAS	LGALS3	P17931	953
KRAS	PIK3CA	P42336	952
KRAS	TP53	P04637	948
KRAS	PTEN	P60484	930
KRAS	NF1	P21359	926
KRAS	ERBB2	P04626	923

IntAct

117 interactions, top by confidence:

A	B	Type	Score
BRAF	HRAS	psi-mi:“MI:0914”(association)	0.940
RIN1	ABL1	psi-mi:“MI:0914”(association)	0.790
KRAS	RAF1	psi-mi:“MI:0915”(physical association)	0.690
BRAF	KRAS	psi-mi:“MI:0914”(association)	0.680
KRAS	BRAF	psi-mi:“MI:2364”(proximity)	0.680
PIP5K1A	KRAS	psi-mi:“MI:0915”(physical association)	0.660
PIP5K1A	KRAS	psi-mi:“MI:0407”(direct interaction)	0.660
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
RHOD	PLXNB2	psi-mi:“MI:0914”(association)	0.640
RAP1GDS1	DIRAS1	psi-mi:“MI:0914”(association)	0.640
ARAF	KRAS	psi-mi:“MI:0915”(physical association)	0.560
KRAS	ARAF	psi-mi:“MI:0915”(physical association)	0.560
KRAS	RASSF2	psi-mi:“MI:0915”(physical association)	0.540
KRAS	RASSF2	psi-mi:“MI:0407”(direct interaction)	0.540
ARL6IP5	KRAS	psi-mi:“MI:0915”(physical association)	0.520
RHOA	KRAS	psi-mi:“MI:0915”(physical association)	0.520
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
	KRAS	psi-mi:“MI:0194”(cleavage reaction)	0.440
KRAS	tcsL	psi-mi:“MI:0414”(enzymatic reaction)	0.440
	KRAS	psi-mi:“MI:0883”(gtpase reaction)	0.440

BioGRID (4294): KRAS (Two-hybrid), MDFI (Two-hybrid), PSMA3 (Two-hybrid), RBPMS (Two-hybrid), KRAS (Two-hybrid), KRAS (Affinity Capture-MS), KRAS (Affinity Capture-MS), KRAS (Two-hybrid), KRAS (Affinity Capture-RNA), THOC1 (Synthetic Growth Defect), TAF1 (Synthetic Growth Defect), MAP2K1 (Synthetic Growth Defect), PRPF31 (Synthetic Growth Defect), JMJD4 (Synthetic Growth Defect), KMT2E (Synthetic Growth Defect)

ESM2 similar proteins: A5A6J7, A6NIZ1, O42277, P01111, P01112, P01116, P03967, P05774, P08556, P08642, P08644, P08645, P12825, P15064, P18262, P18613, P20171, P22123, P22981, P23175, P32883, P34729, P61223, P61224, P62833, P62834, P62835, P62836, P79800, Q04970, Q05147, Q07983, Q18246, Q2MJK3, Q4R9D4, Q5EFX7, Q5F352, Q5RD87, Q5RDM6, Q5ZHX1

Diamond homologs: A5A6J7, A6NIZ1, A8NU18, B3M185, B3NZR4, B4GFJ8, B4HKC7, B4JFU8, B4LY29, B4NJ72, B4PUP5, C4YKT4, G4MZY8, O42277, O42785, O93856, P01111, P01112, P01113, P01115, P01116, P01119, P01120, P03967, P05774, P08556, P08642, P08644, P08645, P08646, P08647, P0CQ42, P0CQ43, P0CY32, P10114, P12825, P13856, P15064, P18613, P20171

SIGNOR signaling

46 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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 101 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	9	39.3×	5e-10
Signaling by high-kinase activity BRAF mutants	7	28.8×	5e-07
Negative regulation of MAPK pathway	8	27.6×	7e-08
MAP2K and MAPK activation	7	25.9×	9e-07
Signaling by RAF1 mutants	7	25.3×	9e-07
Downstream signal transduction	5	24.7×	5e-05
Signaling by moderate kinase activity BRAF mutants	7	23.1×	1e-06
Paradoxical activation of RAF signaling by kinase inactive BRAF	7	23.1×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
Ras protein signal transduction	9	20.3×	6e-07
epidermal growth factor receptor signaling pathway	6	16.3×	5e-04
myelination	5	13.8×	4e-03
MAPK cascade	8	13.5×	8e-05
insulin receptor signaling pathway	5	12.2×	5e-03
positive regulation of cell migration	9	6.1×	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).

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	39
Likely pathogenic	39
Uncertain significance	200
Likely benign	162
Benign	35

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1016209	NM_004985.5(KRAS):c.214A>C (p.Met72Leu)	Pathogenic
1172833	NM_004985.5(KRAS):c.197_198insTGACCTGCT (p.Ala66_Met67insAspLeuLeu)	Pathogenic
1219824	NM_004985.5(KRAS):c.346A>C (p.Asn116His)	Pathogenic
12580	NM_004985.5(KRAS):c.38G>A (p.Gly13Asp)	Pathogenic
12581	NM_033360.4(KRAS):c.175G>A (p.Ala59Thr)	Pathogenic
12583	NM_004985.5(KRAS):c.35G>T (p.Gly12Val)	Pathogenic
12584	NM_004985.5(KRAS):c.34G>A (p.Gly12Ser)	Pathogenic
12585	NM_033360.4(KRAS):c.27_29dup (p.Gly10dup)	Pathogenic
12586	NM_004985.5(KRAS):c.178G>C (p.Gly60Arg)	Pathogenic
12587	NM_004985.5(KRAS):c.458A>T (p.Asp153Val)	Pathogenic
12588	NM_004985.5(KRAS):c.173C>T (p.Thr58Ile)	Pathogenic
12589	NM_004985.5(KRAS):c.40G>A (p.Val14Ile)	Pathogenic
12591	NM_033360.4(KRAS):c.*9T>G	Pathogenic
12593	NM_004985.5(KRAS):c.37G>C (p.Gly13Arg)	Pathogenic
12594	NM_033360.4(KRAS):c.15A>T (p.Lys5Asn)	Pathogenic
12595	NM_033360.4(KRAS):c.*22C>G	Pathogenic
12597	NM_033360.4(KRAS):c.178G>A (p.Gly60Ser)	Pathogenic
163758	NM_004985.5(KRAS):c.466T>A (p.Phe156Ile)	Pathogenic
1691382	NM_004985.5(KRAS):c.36_37delinsGC (p.Gly13Arg)	Pathogenic
1695421	NM_004985.5(KRAS):c.53C>T (p.Ala18Val)	Pathogenic
1695422	NM_004985.5(KRAS):c.194_195insGGCAATGAGGGACCAGTACAG (p.Tyr64_Ser65insArgAlaMetArgAspGlnTyr)	Pathogenic
1701193	NM_004985.5(KRAS):c.33_34delinsCT (p.Gly12Cys)	Pathogenic
177777	NM_004985.5(KRAS):c.181C>A (p.Gln61Lys)	Pathogenic
217822	NM_004985.5(KRAS):c.57G>C (p.Leu19Phe)	Pathogenic
2716407	NM_004985.5(KRAS):c.467T>C (p.Phe156Ser)	Pathogenic
31940	NM_033360.4(KRAS):c.211T>C (p.Tyr71His)	Pathogenic
372705	NM_033360.4(KRAS):c.15A>C (p.Lys5Asn)	Pathogenic
375965	NM_033360.4(KRAS):c.351A>C (p.Lys117Asn)	Pathogenic
40451	NM_033360.4(KRAS):c.64C>G (p.Gln22Glu)	Pathogenic
40452	NM_004985.5(KRAS):c.65A>G (p.Gln22Arg)	Pathogenic

SpliceAI

1269 predictions. Top by Δscore:

Variant	Effect	Δscore
12:25209908:CACC:C	acceptor_gain	1.0000
12:25209909:ACCCT:A	acceptor_loss	1.0000
12:25209910:CC:C	acceptor_gain	1.0000
12:25209910:CCCT:C	acceptor_loss	1.0000
12:25209911:CC:C	acceptor_gain	1.0000
12:25209912:CTGA:C	acceptor_loss	1.0000
12:25209913:T:A	acceptor_loss	1.0000
12:25225609:CTTA:C	donor_loss	1.0000
12:25225610:TTACC:T	donor_loss	1.0000
12:25225611:TACC:T	donor_loss	1.0000
12:25225612:A:AC	donor_gain	1.0000
12:25225612:ACCTG:A	donor_loss	1.0000
12:25225613:C:CC	donor_gain	1.0000
12:25225613:CCT:C	donor_gain	1.0000
12:25225613:CCTG:C	donor_gain	1.0000
12:25225613:CCTGT:C	donor_gain	1.0000
12:25225769:GTTCT:G	acceptor_gain	1.0000
12:25225770:TTCT:T	acceptor_gain	1.0000
12:25225772:CT:C	acceptor_gain	1.0000
12:25225774:C:CC	acceptor_gain	1.0000
12:25225774:CTGGG:C	acceptor_loss	1.0000
12:25227304:T:TA	donor_gain	1.0000
12:25227313:A:AC	donor_gain	1.0000
12:25227314:C:CC	donor_gain	1.0000
12:25227319:C:A	donor_gain	1.0000
12:25227334:ACT:A	donor_gain	1.0000
12:25227335:CTC:C	donor_gain	1.0000
12:25227335:CTCCT:C	donor_gain	1.0000
12:25227411:TC:T	acceptor_gain	1.0000
12:25227412:CC:C	acceptor_gain	1.0000

AlphaMissense

1249 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:25225713:T:A	K117N	1.000
12:25225713:T:G	K117N	1.000
12:25225714:T:A	K117I	1.000
12:25225715:T:C	K117E	1.000
12:25225716:A:C	N116K	1.000
12:25225716:A:T	N116K	1.000
12:25227290:A:C	F78L	1.000
12:25227290:A:T	F78L	1.000
12:25227292:A:G	F78L	1.000
12:25227294:C:T	G77D	1.000
12:25227295:C:G	G77R	1.000
12:25227301:C:A	G75W	1.000
12:25227345:C:T	G60D	1.000
12:25227346:C:A	G60C	1.000
12:25227346:C:G	G60R	1.000
12:25227353:G:C	D57E	1.000
12:25227353:G:T	D57E	1.000
12:25227354:T:A	D57V	1.000
12:25227354:T:C	D57G	1.000
12:25227354:T:G	D57A	1.000
12:25227355:C:G	D57H	1.000
12:25227355:C:T	D57N	1.000
12:25227357:A:G	L56P	1.000
12:25227412:C:G	D38H	1.000
12:25245287:T:C	D33G	1.000
12:25245301:A:C	F28L	1.000
12:25245301:A:T	F28L	1.000
12:25245303:A:G	F28L	1.000
12:25245317:A:G	L23P	1.000
12:25245337:C:A	K16N	1.000

dbSNP variants (sampled 300 via entrez): RS1000015355 (12:25220424 G>A,T), RS1000064955 (12:25228787 G>A), RS1000088508 (12:25220041 G>A), RS1000222340 (12:25204910 C>T), RS1000262608 (12:25213642 A>G,T), RS1000308975 (12:25222123 T>C), RS1000332182 (12:25239355 C>T), RS1000416577 (12:25248764 G>C,T), RS1000628275 (12:25214752 A>G), RS1000660819 (12:25233817 C>T), RS1000671523 (12:25244534 G>A,C,T), RS1000766729 (12:25238233 C>G), RS1000830801 (12:25249768 A>T), RS1000879836 (12:25238269 A>C), RS1000893231 (12:25248550 T>C)

Disease associations

OMIM: gene MIM:190070 | disease phenotypes: MIM:614470, MIM:613659, MIM:109800, MIM:108010, MIM:163200, MIM:211980, MIM:600268, MIM:609942, MIM:615278, MIM:260350, MIM:114480, MIM:601626, MIM:601518, MIM:607785, MIM:613001, MIM:162900, MIM:608354, MIM:608355, MIM:608232, MIM:115150, MIM:163950, MIM:188550, MIM:192600, MIM:114500, MIM:236000, MIM:254500, MIM:236750

GenCC curated gene-disease

Disease	Classification	Inheritance
Noonan syndrome 3	Definitive	Autosomal dominant
cardiofaciocutaneous syndrome 2	Definitive	Autosomal dominant
Noonan syndrome	Definitive	Autosomal dominant
cardiofaciocutaneous syndrome	Strong	Autosomal dominant
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 (3)

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

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

Mondo (49): RASopathy (MONDO:0021060), autoimmune lymphoproliferative syndrome type 4 (MONDO:0013767), gastric cancer (MONDO:0001056), urinary bladder cancer (MONDO:0001187), arteriovenous malformations of the brain (MONDO:0007154), linear nevus sebaceous syndrome (MONDO:0008097), lung cancer (MONDO:0008903), Toriello-Lacassie-Droste syndrome (MONDO:0010854), Noonan syndrome 3 (MONDO:0012371), cardiofaciocutaneous syndrome 2 (MONDO:0014112), familial pancreatic carcinoma (MONDO:0015278), hereditary breast carcinoma (MONDO:0016419), acute myeloid leukemia (MONDO:0018874), prostate cancer, hereditary, 1 (MONDO:0011098), endometrial carcinoma (MONDO:0002447)

Orphanet (33): RASopathy (Orphanet:536391), RAS-associated autoimmune leukoproliferative disease (Orphanet:268114), Familial pancreatic carcinoma (Orphanet:1333), Cardiofaciocutaneous syndrome (Orphanet:1340), Hereditary breast cancer (Orphanet:227535), Linear nevus sebaceus syndrome (Orphanet:2612), Oculoectodermal syndrome (Orphanet:3339), Brain arteriovenous malformation (Orphanet:46724), Acute myeloid leukemia (Orphanet:519), Noonan syndrome (Orphanet:648), Familial prostate cancer (Orphanet:1331), Encephalocraniocutaneous lipomatosis (Orphanet:2396), Juvenile myelomonocytic leukemia (Orphanet:86834), Noonan syndrome and Noonan-related syndrome (Orphanet:98733), Capillary malformation-arteriovenous malformation (Orphanet:137667)

HPO phenotypes

372 total (30 of 372 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000014	Abnormality of the bladder
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:0000176	Submucous cleft hard palate
HP:0000179	Thick lower lip vermilion
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:0000343	Long philtrum

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003927_3	Dysmenorrheic pain	6.000000e-07
GCST009144_15	Disease progression in age-related macular degeneration (adjusted for baseline)	3.000000e-06
GCST90011898_14	Alanine aminotransferase levels	3.000000e-08
GCST90013407_90	Liver enzyme levels (gamma-glutamyl transferase)	4.000000e-20

EFO canonical traits (3, from GWAS)

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

MeSH disease descriptors (20)

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
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D056685	Costello Syndrome	C05.660.207.219; C16.131.077.256; C16.320.188
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
D012509	Sarcoma	C04.557.450.795
D013724	Teratoma	C04.557.465.910
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)

Molecules with ChEMBL bioactivity

11 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 49,427 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1229517	VEMURAFENIB	4	15,704
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL298734	LONAFARNIB	4	12,801
CHEMBL4535757	SOTORASIB	4	3,916
CHEMBL4594350	ADAGRASIB	4	2,814
CHEMBL5077861	OPNURASIB	3	480
CHEMBL5095236	DIVARASIB	2	631
CHEMBL5314518	GLECIRASIB	2	24
CHEMBL351706	BMS-214662	1	399
CHEMBL3577124	LY-3009120	1	198
CHEMBL4858364	MRTX-1133	1	30

Clinical evidence (CIViC)

Drug × variant × indication: 238 predictive associations from 374 curated evidence items; also 27 prognostic, 8 oncogenic, 7 diagnostic, 2 predisposing.

Variant	Therapy	Indication	Effect	Level	CIViC
KRAS G12C	Sotorasib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID9431 +4
KRAS G12C	Cetuximab + Adagrasib	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	Cetuximab + Chemotherapy	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	Cetuximab + Panitumumab	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	Sorafenib + Docetaxel + Carboplatin	Skin Melanoma	Sensitivity/Response	CIViC B	EID1497
KRAS Exon 2 Mutation	Selumetinib + Irinotecan	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	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 G12V	Selumetinib + Docetaxel	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC B	EID1143
KRAS G13D	Chemotherapy + Cetuximab	Colorectal Adenocarcinoma	Sensitivity/Response	CIViC B	EID11054
KRAS G13D	Cetuximab	Colon Cancer	Sensitivity/Response	CIViC B	EID6974
KRAS Mutation	Salirasib	Lung Adenocarcinoma	Sensitivity/Response	CIViC B	EID1218
KRAS Mutation	Sorafenib + Refametinib	Hepatocellular Carcinoma	Sensitivity/Response	CIViC B	EID1642

+208 more predictive associations (showing top 30 by evidence level).

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

2 annotations.

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

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs61764370	ETFRF1, KRAS	3	2.75	1	cetuximab;panitumumab
rs112445441	KRAS	3	3.12	1	cetuximab
rs121913529	KRAS		0.00	0
rs17851045	KRAS		0.00	0
rs121913530	KRAS		0.00	0
rs1057519725	KRAS		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — RAS subfamily

Most potent curated ligand interactions (20 total), top 20:

Ligand	Action	Affinity	Parameter
MRTX1133	Inhibition	12.7	pKd
divarasib	Inhibition	12.62	pKd
LUNA18	Inhibition	10.37	pKd
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
BI-2493	Inhibition	8.0	pKd
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)

1564 measured of 2250 human assays (2514 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-ethynyl-6-fluoro-4-[(4R,7S,8R)-14-fluoro-17-[[(3S,8S)-3-[(1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)oxymethyl]-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
(4R,7S,8R)-14-(8-ethynyl-7-fluoronaphthalen-1-yl)-15-fluoro-18-[[(3S,8S)-3-[(1,1,1,3,3,3-hexafluoro-2-methylpropan-2-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	0.1 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
(4R,7S,8R)-18-[[(3S,8S)-3-[(1-cyclopropyl-2,2,2-trifluoroethoxy)methyl]-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	0.1 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
5-ethynyl-6-fluoro-4-[(4R,7S,8R)-14-fluoro-17-[[(8S)-2-(trifluoromethoxy)-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-[[(2S,8R)-2-(trifluoromethoxy)-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	0.2 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
[(3S,8S)-8-[[(4R,7S,8S)-13-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-14-fluoro-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]-1,2,3,5,6,7-hexahydropyrrolizin-3-yl]methyl N-methyl-N-(trifluoromethyl)carbamate	IC50	0.3 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
4-[(4R,7S,8R)-17-[[(3S,8S)-3-[(1-cyclopropyl-2,2,2-trifluoroethoxy)methyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-14-fluoro-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]-5-ethynyl-6-fluoronaphthalen-2-ol	IC50	0.3 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
(4R,7S,8R)-13-(8-ethynyl-7-fluoronaphthalen-1-yl)-14-fluoro-17-[[(3S,8S)-3-[(1,1,1,3,3,3-hexafluoro-2-methylpropan-2-yl)oxymethyl]-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-pentaene	IC50	0.3 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
2-Amino-4-(6- chloro-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin- 7a(5H)- yl)methoxy)-4- ((R)-6-hydroxy- 1,4-oxazepan-4- yl)quinazolin-7- yl)-7- fluorobenzo[b] thiophene-3- carbonitrile	IC50	0.4 nM	US-20250163064: QUINAZOLINE COMPOUNDS AND USES THEREOF AS INHIBITORS OF MUTANT KRAS PROTEINS
(3S,9S,18S,21S,25S,28S,34S,36R)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36-ethoxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-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	IC50	0.47 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
5-ethynyl-6-fluoro-4-[(4R,7S,8R)-14-fluoro-17-[[(2S,8S)-2-[1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl]oxy-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	0.5 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-18-isopropyl-7,10,13,16,22,26,29-heptamethyl-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-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	IC50	0.5 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-36,36-difluoro-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-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	IC50	0.52 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-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	IC50	0.55 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-(2,2,2-trifluoroethyl)-9-[[4-(trifluoromethyl)phenyl]methyl]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	IC50	0.56 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-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	IC50	0.56 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-propyl-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	IC50	0.59 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]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	IC50	0.64 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
US12466840, Example Ex-2	IC50	0.65 nM	US-12466840: Small molecule inhibitors of KRAS proteins
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-18-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-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	IC50	0.66 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(8S)-13-(6-chloro-5-cyclopropyl-1H-indazol-4-yl)-14-fluoro-17-[[(6E,8S)-6-(fluoromethylidene)-2,3,5,7-tetrahydro-1H-pyrrolizin-8-yl]methoxy]-6,10-dioxa-2,12,16,18-tetrazatetracyclo[9.7.1.02,8.015,19]nonadeca-1(18),11,13,15(19),16-pentaene	IC50	0.67 nM	US-12466840: Small molecule inhibitors of KRAS proteins
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclohexylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)spiro[1,4,7,10,13,16,19,22,26,29,32-undecazabicyclo[32.3.0]heptatriacontane-31,1’-cyclobutane]-2,5,8,11,14,17,20,23,27,30,33-undecone	IC50	0.68 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-propyl-9-[[4-(trifluoromethyl)phenyl]methyl]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	IC50	0.68 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(p-tolylmethyl)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	IC50	0.69 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-9-(cyclohexylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-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	IC50	0.69 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(4R,7S,8R)-17-[[(3S,8S)-3-[(1-cyclopropyl-2,2,2-trifluoroethoxy)methyl]-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-13-(8-ethynyl-7-fluoronaphthalen-1-yl)-14-fluoro-2,12,16,18,20-pentazapentacyclo[9.7.1.14,7.02,8.015,19]icosa-1(18),11(19),12,14,16-pentaene	IC50	0.7 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(p-tolylmethyl)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	IC50	0.76 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(propoxymethyl)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	IC50	0.76 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]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	IC50	0.77 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-21-cyclobutyl-28-cyclohexyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(propoxymethyl)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	IC50	0.81 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S,36R)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-36-ethoxy-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-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	IC50	0.82 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-21-ethyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-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	IC50	0.86 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(4-(trifluoromethyl)benzyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	0.87 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(4R,7S,8R)-13-(8-ethynyl-7-fluoronaphthalen-1-yl)-14-fluoro-17-[[(3S,8S)-3-[[1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl)propan-2-yl]oxymethyl]-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-pentaene	IC50	0.9 nM	US-20230339981: KRAS G12D MODULATING COMPOUNDS
(3S,95,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-(propoxymethyl)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	IC50	0.99 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-propyl-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	IC50	0.99 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
2-amino-4-[4-(azepan-1-yl)-6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-1-benzothiophene-3-carbonitrile	IC50	1 nM	US-20250163064: QUINAZOLINE COMPOUNDS AND USES THEREOF AS INHIBITORS OF MUTANT KRAS PROTEINS
2-Amino-4-(4- (azocan-1-yl)-6- chloro-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin- 7a(5H)- yl)methoxy) quinazolin-7-yl)-7- fluorobenzo[b] thiophene-3- carbonitrile	IC50	1 nM	US-20250163064: QUINAZOLINE COMPOUNDS AND USES THEREOF AS INHIBITORS OF MUTANT KRAS PROTEINS
(2S)-1-(7-(2- Amino-3-cyano- 7- fluorobenzo[b] thiophen-4-yl)-6- chloro-8-fluoro- 2-(((2R,7aS)-2- fluorotetrahydro- 1H-pyrrolizin- 7a(5H)- yl)methoxy) quinazolin-4- yl)pyrrolidine-2- carbonitrile	IC50	1 nM	US-20250163064: QUINAZOLINE COMPOUNDS AND USES THEREOF AS INHIBITORS OF MUTANT KRAS PROTEINS
N-[(1S)-1-[[(8S,14S)-22-ethyl-4-hydroxy-(21M)-21-[2-[(1S)-1-methoxyethyl]-3-pyridyl]-18,18-dimethyl-9,15-dioxo-16-oxa-10,22,28-triazapentacyclo[18.5.2.12,6.110,14.023,27]nonacosa-1(26),2,4,6(29),20,23	IC50	1 nM	US-20250163072: MACROCYCLIC COMPOUNDS FOR THE TREATMENT OF CANCER
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8,18-di((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxylmethyl)docosahydro-21H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	1.1 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-9-[[4-(trifluoromethyl)phenyl]methyl]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	IC50	1.1 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-21-(2,2,2-trifluoroethyl)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	IC50	1.2 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-28-cyclohexyl-9-(cyclohexylmethyl)-3-[2-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl]-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-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	IC50	1.2 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
US12466840, Example Ex-6	IC50	1.3 nM	US-12466840: Small molecule inhibitors of KRAS proteins
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18-cyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyl-35-(propoxymethyl)docosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	1.4 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
US12466840, Example Ex-7	IC50	1.4 nM	US-12466840: Small molecule inhibitors of KRAS proteins
(5S,8S,11S,15S,18S,23aS,29S,35S,37aS)-15-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)-8-((S)-sec-butyl)-29-(3-chloro-4-(trifluoromethyl)phenethyl)-18,35-dicyclopentyl-11-isobutyl-5,6,12,16,19,33,36-heptamethyldocosahydro-2H,4H-spiro[azeto[2,1-u]pyrrolo[2,1-i][1,4,7,10,13,16,19,22,25,28,31]undecaazacyclotetratriacontine-21,1’-cyclopentan]-4,7,10,13,17,20,23,28,31,34,37(14H,22H)-undecaone	IC50	1.5 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
(3S,9S,18S,21S,25S,28S,34S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-28-cyclohexyl-9-(cyclopentylmethyl)-21-isobutyl-7,10,13,16,22,26,29-heptamethyl-18-[(1S)-1-methylpropyl]-25-(3-oxa-8-azabicyclo[3.2.1]octane-8-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	IC50	1.5 nM	US-20240148821: PHARMACEUTICAL USE OF CYCLIC PEPTIDE COMPOUND
6-[8-chloro-13-[2-(dimethylamino)ethyl]-6-fluoro-3-[[(8S)-6-methylidene-2,3,5,7-tetrahydro-1H-pyrrolizin-8-yl]methoxy]-10-oxa-2,4,13-triazatricyclo[7.4.1.05,14]tetradeca-1,3,5(14),6,8-pentaen-7-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine	IC50	1.55 nM	US-20240383915: OXAZEPINE COMPOUNDS AND USES THEREOF IN THE TREATMENT OF CANCER

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

1064 with measured affinity, of 4927 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
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
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
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
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
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
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
2-amino-4-[6-chloro-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]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	0.0010	uM
8-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-1,8-diazaspiro[3.5]nonan-2-one	1952970: Inhibition of His-tagged KRAS G12D mutant (unknown origin) using biotinylated KRPep-2d as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by LANCE TR-FRET assay	ic50	0.0010	uM
4-[(3S)-3-(cyanomethyl)-4-prop-2-enoylpiperazin-1-yl]-N-[(1R,2R)-2-(dimethylamino)cyclopentyl]-7-(8-methylnaphthalen-1-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	0.0010	uM
5-ethynyl-6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(1-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol	1952970: Inhibition of His-tagged KRAS G12D mutant (unknown origin) using biotinylated KRPep-2d as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by LANCE TR-FRET assay	ic50	0.0010	uM
3-chloro-4-cyclopropyl-5-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(1-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[4,3-d]pyrimidin-7-yl]phenol	1952970: Inhibition of His-tagged KRAS G12D mutant (unknown origin) using biotinylated KRPep-2d as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by LANCE TR-FRET assay	ic50	0.0010	uM
5,6-difluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(1-oxa-8-azaspiro[3.5]nonan-8-yl)pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol	1952970: Inhibition of His-tagged KRAS G12D mutant (unknown origin) using biotinylated KRPep-2d as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by LANCE TR-FRET assay	ic50	0.0010	uM
6-[7-(8-ethyl-3-hydroxynaphthalen-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-6-azaspiro[3.5]nonan-2-ol	1952971: Inhibition of N-terminal His-tagged GDP-bound KRAS G12D mutant (1 to 169 residues) (unknown origin) assessed as inhibition of SOS mediated nucleotide exchange preincubated for 2 hrs followed by addition of SOS protein and unlabeled GTP measured after 30 mins by Alphascreen assay	ic50	0.0010	uM
5-chloro-6-fluoro-4-[8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-[(4S)-1-oxa-8-azaspiro[3.5]nonan-8-yl]pyrido[4,3-d]pyrimidin-7-yl]naphthalen-2-ol	1952970: Inhibition of His-tagged KRAS G12D mutant (unknown origin) using biotinylated KRPep-2d as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by LANCE TR-FRET assay	ic50	0.0010	uM
9-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-1-oxa-3,9-diazaspiro[4.5]decan-2-one	1952970: Inhibition of His-tagged KRAS G12D mutant (unknown origin) using biotinylated KRPep-2d as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by LANCE TR-FRET assay	ic50	0.0010	uM
5-[7-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrido[4,3-d]pyrimidin-4-yl]-5-azaspiro[2.5]octan-7-ol	1952970: Inhibition of His-tagged KRAS G12D mutant (unknown origin) using biotinylated KRPep-2d as substrate preincubated for 30 mins followed by substrate addition and measured after 2 hrs by LANCE TR-FRET assay	ic50	0.0010	uM
2-[(4R,9R,12S,15S,21S,24S,27S,30S,33S,36S,39S,40S)-4-[[(2S)-2-[[(2S)-2-acetamido-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-9-[[(2S)-1-[[(2S)-1-amino-5-carbamimidamido-1-oxopentan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]-30-[(2S)-butan-2-yl]-27-(hydroxymethyl)-24-[(4-hydroxyphenyl)methyl]-36-(2-methylpropyl)-3,11,14,20,23,26,29,32,35,38-decaoxo-12-pentyl-33-[(4-phenylphenyl)methyl]-40-prop-2-enyl-6,7-dithia-1,10,13,19,22,25,28,31,34,37-decazatricyclo[37.3.0.015,19]dotetracontan-21-yl]acetic acid	1880867: Inhibition of recombinant biotinylated KRAS G12D mutant (unknown origin) assessed as inhibition of SOS-catalyzed nucleotide exchange preincubated for 60 mins followed by addition of human SOS protein and unlabeled GTP and measured after 60 mins by TR-FRET analysis	ic50	0.0010	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Vinyl Chloride	increases mutagenesis, affects mutagenesis, increases reaction	7
Resveratrol	affects cotreatment, increases expression, decreases expression	5
Tobacco Smoke Pollution	affects expression, increases expression, increases mutagenesis	5
bisphenol A	decreases expression, increases mutagenesis, affects cotreatment, increases expression	4
Quercetin	increases expression, affects activity, decreases reaction, decreases expression, affects cotreatment	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	decreases reaction, increases expression, increases mutagenesis	2
hydroquinone	affects response to substance, affects expression, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	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 response to substance, decreases response to substance, affects reaction	2
Arsenic	increases mutagenesis, affects reaction, increases phosphorylation, increases secretion, affects response to substance	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 cotreatment, affects expression	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
chymostatin	decreases reaction, increases expression	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

5,318 cell lines: 5,268 cancer cell line, 22 spontaneously immortalized cell line, 12 induced pluripotent stem cell, 7 transformed cell line, 4 telomerase immortalized cell line, 2 hybrid 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)

326 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04320316	PHASE4	COMPLETED	A Trial to Assess the Safety and Efficacy of KRN23 in Epidermal Nevus Syndrome (ENS)
NCT00365508	PHASE4	COMPLETED	Counseling and Nicotine Replacement Therapy in Helping Adult Smokers Quit Smoking
NCT00558155	PHASE4	COMPLETED	The Impact of Immunostimulating Nutrition on the Outcome of Surgery
NCT00576940	PHASE4	COMPLETED	Standard and Immunostimulating Enteral Nutrition in Surgical Patients
NCT00666978	PHASE4	COMPLETED	Health Education Counseling With or Without Bupropion in Helping African Americans Stop Smoking
NCT01038154	PHASE4	UNKNOWN	Study to Evaluate the Efficacy of Pravastatin on Survival and Recurrence of Advanced Gastroesophageal Cancer
NCT01234272	PHASE4	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	PHASE4	TERMINATED	A Study of Herceptin (Trastuzumab) in Combination With Standard Chemotherapy in Patients With HER Positive Metastatic Gastric Cancer
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01401075	PHASE4	COMPLETED	RCT With Adjuvant Mistletoe Treatment in Gastric Cancer Patients
NCT01471756	PHASE4	COMPLETED	Improving Complete Endoscopic Mucosal Resection (EMR) of Colorectal Neoplasia
NCT01766765	PHASE4	UNKNOWN	Early Jejunostomy Nutrition Minimizes Time to Chemotherapy
NCT01910948	PHASE4	UNKNOWN	Perioperative Application of Omega-3 Polyunsaturated Fatty Acids in Gastric Cancer Patients
NCT01927328	PHASE4	UNKNOWN	Iron Replacement in Oesophagogastric Neoplasia
NCT01962272	PHASE4	COMPLETED	The Effect of Nutritional Counseling for Cancer Patients
NCT01962376	PHASE4	UNKNOWN	Preoperative Chemotherapy With Bevacizumab For Potentially Resectable Gastric Cancer With Liver Metastasis
NCT02047994	PHASE4	RECRUITING	Multicentric Randomized Study of H. Pylori Eradication and Pepsinogen Testing for Prevention of Gastric Cancer Mortality
NCT02235246	PHASE4	COMPLETED	The Effect of Perioperative Intravenous Magnesium on Pain After Endoscopic Submucosal Dissection for Gastric Neoplasm: Prospective Randomized Double-blind Placebo Controlled Study
NCT02366819	PHASE4	SUSPENDED	Genetic Analysis-Guided Irinotecan Hydrochloride Dosing of mFOLFIRINOX in Treating Patients With Locally Advanced Gastroesophageal or Stomach Cancer
NCT02401971	PHASE4	UNKNOWN	Irinotecan Plus Thalidomide in Second Line Advanced Gastric Cancer
NCT02458573	PHASE4	COMPLETED	Comparison of the Effects of Continuous Epidural Analgesia and Continuous Intravenous Analgesia on Postoperative Bowel Movement in Patients Undergoing Laparoscopic Gastrectomy
NCT02638584	PHASE4	COMPLETED	Effects of Ilaprazole on Ulcer Healing Rate and Prevention of Gastrointestinal Bleeding in the Patients Undergone ESD.
NCT02776527	PHASE4	UNKNOWN	A Clinical Trial of Maintenance Treatment of Apatinib in Advanced Gastric Cancer Patients Have Completed Postoprative Adjuvant Chemotherapy
NCT03384511	PHASE4	COMPLETED	The Use of 18F-ALF-NOTA-PRGD2 PET/CT Scan to Predict the Efficacy and Adverse Events of Apatinib in Malignancies.
NCT03550482	PHASE4	COMPLETED	Oncoxin® and Quality of Life in Cancer Patients
NCT03609892	PHASE4	COMPLETED	Helicobacter Rescue Therapy With Berberine Plus Amoxicillin Quadruple Therapy Versus Tetracycline Plus Furazolidone Quadruple Therapy
NCT03642093	PHASE4	UNKNOWN	HOPE - A Study to Evaluate the Effect of a Prehabilitation Program on GI Cancer Patients Planning to Undergo Surgery
NCT03733639	PHASE4	UNKNOWN	Tisseel® as a Reinforcement of Esophagojejunal Anastomoses
NCT04168346	PHASE4	NOT_YET_RECRUITING	Preoperative Intravenous Iron Therapy in Patients With Gastric Cancer
NCT04209933	PHASE4	COMPLETED	Helicobacter Pylori Eradication With Different Bismuth Quadruple Therapies
NCT04591028	PHASE4	WITHDRAWN	A Study to Evaluate Indocyanine Green Lymphangiography to Improve Lymphadenectomy in Gastric Cancer Patients
NCT04607057	PHASE4	UNKNOWN	Supplemental Parenteral Nutrition During Postgastrectomy in Nutritionally at Risk Patient
NCT04660123	PHASE4	COMPLETED	A Real World Study of Bismuth Colloidal Pectin Granules Quadruple Therapy for H. Pylori Eradication
NCT04678492	PHASE4	COMPLETED	Helicobacter Rescue Therapy With High-dose Esomeprazole and Amoxicillin Dual Therapy Versus Bismuth-containing Quadruple Therapy
NCT04697186	PHASE4	COMPLETED	Helicobacter Pylori Eradication With Berberine Plus Amoxicillin Triple Therapy Versus Bismuth-containing Quadruple Therapy
NCT05029453	PHASE4	UNKNOWN	Apatinib Combined With Chemotherapy Versus Chemotherapy in Second-line Gastric Cancer Receiving Prior Anti-PD-1 Therapy
NCT05183126	PHASE4	RECRUITING	Pharmacokinetic Study of Skeletal Muscle Area-based Paclitaxel Infusion in Patients With Cancer
NCT05354856	PHASE4	TERMINATED	The Effect of Chemoradiotherapy on Gastric Perfusion in Patients With Gastric Cancer.
NCT05410535	PHASE4	COMPLETED	To Evaluate Efficacy of Ursodeoxycholic Acid (UDCA) for the Prevention of Gallstone Formation After Gasterectomy
NCT05498766	PHASE4	NOT_YET_RECRUITING	Effect and Safety of Huaier Granule Versus SOX Regimen in Gastric Cancer Patients