RAF1

Summary

RAF1 (Raf-1 proto-oncogene, serine/threonine kinase, HGNC:9829) is a protein-coding gene on chromosome 3p25.2, encoding RAF proto-oncogene serine/threonine-protein kinase (P04049). Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survi….

This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2.

Source: NCBI Gene 5894 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome (Definitive, ClinGen) — +7 more curated relationships
• Clinical variants (ClinVar): 1,408 total — 13 pathogenic, 27 likely-pathogenic (top 2% of genes corpus-wide)
• GTEx eGene: eQTL in 17 tissues, sQTL in 27 (q < 0.05)
• Drug target: yes — 7 curated mechanism-of-action drugs, 3 via a complex or family; 31 molecules with ChEMBL bioactivity (top 1% of genes corpus-wide)
• Approved drugs (ChEMBL mechanism of action): 2 — Regorafenib, Sorafenib Tosylate
• Approved drugs acting on a complex or family including it: 1 — Tovorafenib (RAF serine/threonine protein kinase)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.35 (moderately constrained)
• MANE Select transcript: NM_002880
• Interaction hub: 3,422 STRING partners (top 2% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9829
Approved symbol	RAF1
Name	Raf-1 proto-oncogene, serine/threonine kinase
Location	3p25.2
Locus type	gene with protein product
Status	Approved
Aliases	Raf-1, c-Raf, CRAF
Ensembl gene	ENSG00000132155
Ensembl biotype	protein_coding
OMIM	164760
Entrez	5894

Gene structure

Transcript identifiers

Ensembl transcripts: 108 — 51 protein_coding, 30 nonsense_mediated_decay, 27 retained_intron

MANE Select: ENST00000251849

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 3, TSL 3: 3, TSL 4: 2, TSL 5: 2

ENST00000251849, ENST00000416093, ENST00000423275, ENST00000432427, ENST00000442415, ENST00000460610, ENST00000465826, ENST00000471449, ENST00000475353, ENST00000491290, ENST00000492690, ENST00000494557, ENST00000684903, ENST00000685348, ENST00000685437, ENST00000685438, ENST00000685653, ENST00000685697, ENST00000685738, ENST00000685740, ENST00000685959, ENST00000686409, ENST00000686455, ENST00000686479, ENST00000686762, ENST00000687257, ENST00000687326, ENST00000687348, ENST00000687486, ENST00000687505, ENST00000687923, ENST00000687940, ENST00000688269, ENST00000688326, ENST00000688444, ENST00000688543, ENST00000688625, ENST00000688753, ENST00000688779, ENST00000688803, ENST00000688914, ENST00000689033, ENST00000689097, ENST00000689226, ENST00000689389, ENST00000689418, ENST00000689481, ENST00000689540, ENST00000689876, ENST00000689914, ENST00000690397, ENST00000690460, ENST00000690585, ENST00000690625, ENST00000691268, ENST00000691396, ENST00000691643, ENST00000691718, ENST00000691724, ENST00000691779, ENST00000691888, ENST00000691899, ENST00000692069, ENST00000692093, ENST00000692311, ENST00000692558, ENST00000692773, ENST00000692777, ENST00000692830, ENST00000692959, ENST00000693069, ENST00000693312, ENST00000693664, ENST00000693705, ENST00000900375, ENST00000900376, ENST00000900377, ENST00000900378, ENST00000900379, ENST00000900380, ENST00000900381, ENST00000900382, ENST00000900383, ENST00000923056, ENST00000923057, ENST00000923058, ENST00000941482, ENST00000941483, ENST00000941484, ENST00000941485, ENST00000941486, ENST00000941487, ENST00000941488, ENST00000941489, ENST00000941490, ENST00000941491, ENST00000941492, ENST00000941493, ENST00000941494, ENST00000941495, ENST00000941496, ENST00000941497, ENST00001027135, ENST00001027136, ENST00001027141, ENST00001027142, ENST00001027143, ENST00001143682

RefSeq mRNA: 8 — MANE Select: NM_002880 NM_001354689, NM_001354690, NM_001354691, NM_001354692, NM_001354693, NM_001354694, NM_001354695, NM_002880

CCDS: CCDS2612, CCDS87047, CCDS93217

Canonical transcript exons

ENST00000251849 — 17 exons

Exon	Start	End
ENSE00000966591	12611950	12612062
ENSE00001671036	12583601	12584657
ENSE00001764624	12663813	12664117
ENSE00003470841	12608766	12608923
ENSE00003492188	12584847	12584981
ENSE00003529470	12585681	12585799
ENSE00003557200	12587591	12587637
ENSE00003569424	12585122	12585253
ENSE00003569537	12591708	12591792
ENSE00003585647	12618515	12618747
ENSE00003602339	12599691	12599808
ENSE00003614346	12600152	12600279
ENSE00003658250	12606201	12606299
ENSE00003659262	12590798	12590974
ENSE00003669646	12600388	12600415
ENSE00003670010	12609233	12609335
ENSE00003685564	12604136	12604289

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 98.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.7348 / max 811.9294, expressed in 1824 samples.

Highest expression (Bgee): gastrocnemius, muscle of leg, ventricular zone, hindlimb stylopod muscle, muscle organ.

Genetic regulation across tissues (GTEx eQTL / sQTL)

RAF1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 17 tissues and its splicing (sQTL) in 27 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 44 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	sqtl	7.8e-123	-1.09	3:12611276:A:G
Skin Sun Exposed Lower leg	sqtl	2.2e-31	+0.64	3:12666074:C:T
Whole Blood	sqtl	1.7e-30	+0.59	3:12686463:C:A
Heart Atrial Appendage	sqtl	7.3e-28	-0.85	3:12619169:T:C
Cells Cultured fibroblasts	sqtl	4.5e-26	-0.77	3:12663549:G:A
Skin Not Sun Exposed Suprapubic	sqtl	1.0e-25	-0.60	3:12582571:C:T
Artery Tibial	sqtl	5.7e-25	-0.93	3:12663549:G:A
Heart Left Ventricle	sqtl	1.5e-18	-0.71	3:12619169:T:C
Cells EBV-transformed lymphocytes	sqtl	4.9e-18	-0.71	3:12593019:T:C
Esophagus Mucosa	sqtl	5.0e-17	+0.55	3:12686463:C:A
Brain Cerebellum	sqtl	1.0e-15	+0.94	3:12604501:T:C
Cells Cultured fibroblasts	eqtl	6.3e-14	-0.23	3:12659570:C:CAATAAAAGACCT
Thyroid	sqtl	5.8e-12	+0.46	3:12673793:G:A
Nerve Tibial	sqtl	3.0e-11	-0.47	3:12606048:T:TG
Adipose Subcutaneous	sqtl	3.4e-11	-0.44	3:12606048:T:TG
Esophagus Muscularis	sqtl	6.6e-10	-0.47	3:12606048:T:TG
Skin Sun Exposed Lower leg	eqtl	1.1e-09	-0.12	3:12534091:A:T
Breast Mammary Tissue	sqtl	2.6e-09	-0.51	3:12606048:T:TG
Brain Cerebellar Hemisphere	sqtl	1.6e-08	-0.80	3:12616219:A:G
Adipose Subcutaneous	eqtl	1.7e-08	+0.18	3:12614517:T:G

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
41134	39.9801	1823
41133	2.4122	1200
202681	0.7756	383
41132	0.3307	177
41131	0.2362	105

Top tissues by expression

showing 100 of 301 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	98.17	gold quality
muscle of leg	UBERON:0001383	98.00	gold quality
ventricular zone	UBERON:0003053	97.85	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.67	gold quality
muscle organ	UBERON:0001630	97.62	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.53	gold quality
ganglionic eminence	UBERON:0004023	97.48	gold quality
blood	UBERON:0000178	97.18	gold quality
cortical plate	UBERON:0005343	97.08	gold quality
right coronary artery	UBERON:0001625	96.91	gold quality
heart left ventricle	UBERON:0002084	96.84	gold quality
right atrium auricular region	UBERON:0006631	96.83	gold quality
skeletal muscle tissue	UBERON:0001134	96.80	gold quality
popliteal artery	UBERON:0002250	96.79	gold quality
cardiac ventricle	UBERON:0002082	96.78	gold quality
left ovary	UBERON:0002119	96.78	gold quality
tibial artery	UBERON:0007610	96.78	gold quality
right ovary	UBERON:0002118	96.77	gold quality
cerebellar hemisphere	UBERON:0002245	96.76	gold quality
cardiac atrium	UBERON:0002081	96.73	gold quality
cerebellar cortex	UBERON:0002129	96.73	gold quality
descending thoracic aorta	UBERON:0002345	96.72	gold quality
vastus lateralis	UBERON:0001379	96.70	gold quality
apex of heart	UBERON:0002098	96.70	gold quality
quadriceps femoris	UBERON:0001377	96.69	gold quality
heart	UBERON:0000948	96.64	gold quality
skin of leg	UBERON:0001511	96.64	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.62	gold quality
aorta	UBERON:0000947	96.58	gold quality
left uterine tube	UBERON:0001303	96.55	gold quality
body of stomach	UBERON:0001161	96.54	gold quality
left lobe of thyroid gland	UBERON:0001120	96.51	gold quality
right lobe of thyroid gland	UBERON:0001119	96.47	gold quality
skin of abdomen	UBERON:0001416	96.46	gold quality
body of uterus	UBERON:0009853	96.41	gold quality
thoracic aorta	UBERON:0001515	96.34	gold quality
left coronary artery	UBERON:0001626	96.32	gold quality
ascending aorta	UBERON:0001496	96.29	gold quality
right lung	UBERON:0002167	96.29	gold quality
muscle tissue	UBERON:0002385	96.27	gold quality
gluteal muscle	UBERON:0002000	96.25	gold quality
cerebellum	UBERON:0002037	96.25	gold quality
thyroid gland	UBERON:0002046	96.24	gold quality
ectocervix	UBERON:0012249	96.23	gold quality
monocyte	CL:0000576	96.22	gold quality
mucosa of stomach	UBERON:0001199	96.20	gold quality
coronary artery	UBERON:0001621	96.17	gold quality
stomach	UBERON:0000945	96.15	gold quality
leukocyte	CL:0000738	96.14	gold quality
mononuclear cell	CL:0000842	96.13	gold quality
granulocyte	CL:0000094	96.10	gold quality
fundus of stomach	UBERON:0001160	96.03	gold quality
endocervix	UBERON:0000458	96.01	gold quality
nerve	UBERON:0001021	96.01	gold quality
diaphragm	UBERON:0001103	96.01	gold quality
tibial nerve	UBERON:0001323	96.01	gold quality
deltoid	UBERON:0001476	96.01	gold quality
embryo	UBERON:0000922	95.99	gold quality
upper lobe of left lung	UBERON:0008952	95.96	gold quality
lower esophagus	UBERON:0013473	95.91	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.91	gold quality
body of pancreas	UBERON:0001150	95.90	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.90	gold quality
triceps brachii	UBERON:0001509	95.77	gold quality
zone of skin	UBERON:0000014	95.75	gold quality
left ventricle myocardium	UBERON:0006566	95.75	gold quality
upper lobe of lung	UBERON:0008948	95.74	gold quality
esophagus	UBERON:0001043	95.70	gold quality
body of tongue	UBERON:0011876	95.70	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.65	gold quality
rectum	UBERON:0001052	95.59	gold quality
tibialis anterior	UBERON:0001385	95.58	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.58	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.57	gold quality
esophagus mucosa	UBERON:0002469	95.53	gold quality
lower esophagus mucosa	UBERON:0035834	95.50	gold quality
bone marrow cell	CL:0002092	95.43	gold quality
right lobe of liver	UBERON:0001114	95.36	gold quality
biceps brachii	UBERON:0001507	95.35	gold quality
small intestine	UBERON:0002108	95.35	gold quality
ovary	UBERON:0000992	95.30	gold quality
minor salivary gland	UBERON:0001830	95.24	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.20	gold quality
smooth muscle tissue	UBERON:0001135	95.17	gold quality
spleen	UBERON:0002106	95.17	gold quality
upper arm skin	UBERON:0004263	95.15	gold quality
metanephros cortex	UBERON:0010533	95.13	gold quality
tongue	UBERON:0001723	95.01	gold quality
cardia of stomach	UBERON:0001162	94.93	gold quality
transverse colon	UBERON:0001157	94.88	gold quality
peritoneum	UBERON:0002358	94.84	gold quality
omental fat pad	UBERON:0010414	94.84	gold quality
mouth mucosa	UBERON:0003729	94.83	gold quality
gall bladder	UBERON:0002110	94.81	gold quality
upper leg skin	UBERON:0004262	94.79	gold quality
pharyngeal mucosa	UBERON:0000355	94.70	gold quality
myocardium	UBERON:0002349	94.69	gold quality
right uterine tube	UBERON:0001302	94.67	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.63	gold quality
bone marrow	UBERON:0002371	94.61	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.29

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 129 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	856.4	medium
Skeletal muscle	tissue	163.1	not detected
Tongue	tissue	102.5
Heart muscle	tissue	85.3	low
Liver	tissue	59.3	low
Parathyroid gland	tissue	54.3	not detected
Caudate putamen	tissue	42.4
Frontal cortex	tissue	42.3
Kidney	tissue	42.2	high
Pancreas	tissue	42.1	high
Thymus	tissue	41.8
Skin 1	tissue	39.5	low
Esophagus	tissue	38.6	low
Ovary	tissue	36.8	not detected
Tonsil	tissue	36.7	medium
Smooth muscle	tissue	36.4	not detected
Thyroid gland	tissue	36.3	not detected
Small intestine	tissue	34.1	not detected
Urinary bladder	tissue	33.9	medium
Rectum	tissue	33.6	medium
Bone marrow	tissue	33.0	not detected
Colon	tissue	32.1	medium
Epididymis	tissue	32.1	medium
Stomach 1	tissue	31.9	medium
Prostate	tissue	31.9	medium
Fallopian tube	tissue	31.5	medium
Duodenum	tissue	31.3	high
Choroid plexus	tissue	31.2
Placenta	tissue	31.0	medium
Seminal vesicle	tissue	30.3	not detected
Cerebellum	tissue	29.9	low
Cervix	tissue	29.3	low
Lung	tissue	28.6	medium
Endometrium 1	tissue	28.4	not detected
Superior colliculi	tissue	28.3
Lymph node	tissue	28.1	medium
Hippocampus	tissue	26.9	not detected
Breast	tissue	26.7	medium
Spinal cord	tissue	26.7
Salivary gland	tissue	26.5	medium
Nucleus accumbens	tissue	26.3
Spleen	tissue	25.7	not detected
Gallbladder	tissue	25.6	medium
Appendix	tissue	25.5	low
Corpus callosum	tissue	25.0
Medulla oblongata	tissue	24.7
Retina	tissue	24.4
Midbrain	tissue	24.3
Adipose tissue	tissue	24.2	not detected
Thalamus	tissue	24.2
Substantia nigra	tissue	24.2
Olfactory bulb	tissue	24.1
Hippocampal formation	tissue	22.7
Cerebral cortex	tissue	22.6	low
Pons	tissue	22.6
Somatosensory cortex	tissue	22.6
Locus coeruleus	tissue	22.2
Periaqueductal gray	tissue	21.7
Occipital cortex	tissue	21.5
Motor cortex	tissue	21.3

Brain sub-regions (HPA Brain Atlas): detected in 374; highest nTPM — Blood vessel (36.9), Cerebellar cortex (31.3), Posterior thalamic nucleus (30.5), Flocculonodular lobe (30.1), Area postrema (29.5).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting RAF1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 79 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-4492	99.87	68.25	3611

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.353, missense Z 3.43 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000442415 splits into 5 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
3:12,584,517–12,585,734	147 / 196.1	0.75	no
3:12,585,735–12,599,759	85 / 185.6	0.46	no
3:12,599,760–12,606,292	194 / 202.7	0.96	no
3:12,606,293–12,618,549	89 / 169.2	0.53	no
3:12,618,550–12,618,721	83 / 72.3	1.15	no

Literature-anchored findings (GeneRIF, showing 40)

• These data show that Ser-259 dephosphorylation contributes to Raf-1 activation by supporting its membrane accumulation rather than by increasing the specific activity of the kinase (PMID:11756411)
• PAK1 primes MEK1 for phosphorylation by Raf-1 kinase during cross-cascade activation of the ERK pathway. (PMID:11948406)
• targeted expression inhibits juvenile myelomonocytic leukemia cell growth (PMID:12010819)
• effects of paclitaxel on Raf-1 phosphorylation in ovarian cancer cells (PMID:12087097)
• Results indicate that the phosphorylation of Ser(338) and Tyr(341) on Raf-1 exerts an important effect on reconfiguring the two MEK1-binding sites. (PMID:12244094)
• These data suggest that GILZ contributes, through protein-to-protein interaction with Raf-1 and the consequent inhibition of Raf-MEK-ERK activation, to regulating the MAPK pathway and to providing a further mechanism underlying GCH immunosuppression. (PMID:12391160)
• Raf activation increased the expression of cyclin A, cyclin D, cyclin E, and p21(Cip1), which are associated with G(1) progression (PMID:12429936)
• Activation of the ras/raf-1 signal transduction pathway leads to prominent phenotypic changes that resemble differentiation of gastrointestinal carcinoid cells in vitro. (PMID:12490852)
• phosphorylation by p21-activated kinase 1 and Src regulates Raf-1 autoinhibition (PMID:12551923)
• c-Raf1 activation occurs without serine 338 phosphorylation (PMID:12626521)
• serum stimulation of fibroblasts in floating matrices does not result in ERK translocation to the nucleus and there was decreased serum activation of upstream members of the ERK signaling pathway, MEK and Raf. (PMID:12663662)
• The 1,25(OH)(2)D3-responsive element in cystatin A gene is identical to TRE, T2 (-272 to -278). Suppression of Raf-1/MEK1/ERK1,2 signaling pathway increases cystatin A expression of normal human keratinocytes. (PMID:12682854)
• Raf1 may have a role in antineoplastic drug resistance (PMID:12691824)
• Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4. (PMID:12717443)
• findings implicate Raf-1 as a pivotal regulator of endothelial cell survival during angiogenesis (PMID:12843393)
• results show that raf-1 protein induction suppresses neuroendocrine marker and hormone production in human gastrointestinal carcinoid cells via a pathway dependent on MEK activation (PMID:12851216)
• Raf is regulated through phosphorylation and N terminus-C terminus interaction (PMID:12865432)
• a functional phosphatidate binding site is necessary for Raf-1 function in embryonic development (PMID:12925535)
• Raf-1 has a role in modulating integrin-stimulated ERK activation when bound to CAMKII (PMID:12954639)
• together, our data suggest that the synergistic activation of Raf-1 kinase in response to PMA and H(2)O(2) occurs via mechanisms that involve an interaction of Raf-1 kinase and PKC-epsilon. (PMID:14623285)
• mutation analysis of the conserved regions in the RAF1 gene in human colorectal adenocarcinoma (PMID:14688025)
• Ovarian cancers demonstrate differential sensitivity to antisense oligonucleotides targeted against Raf-1, and target expression levels. (PMID:15041731)
• Despite the effects of constitutively active Raf on pro-B cell expansion in Raf transgenic mice, Raf activation is not sufficient to rescue early B cell development in IL-7 receptor-deficient mice. (PMID:15067053)
• RAF1 promotes herpesvirus 8 infection. (PMID:15122343)
• Changes in flexibility upon protein-protein complex formation of H-Ras & the Ras-binding domain of C-Raf1 have been investigated using the molecular framework approach FIRST and molecular dynamics simulations of in total approximately 35 ns length. (PMID:15211515)
• Raf1 kinase is released when it is hyperphosphorylated and activated during oxidative and other stresses (PMID:15314064)
• Raf1 and MAPK-activated protein kinase 2 are activated by L-ascorbic acid in acute myeloid leukemia cells. (PMID:15451031)
• Raf1 potentiates drug-stimulated cyclic AMP accumulation in cells expressing adenyl cyclcase 6 after activation of multiple signaling pathways. (PMID:15470083)
• Raf-1 links mitogenic signaling to Retinoblastoma Protein and that disruption of this interaction could aid in controlling proliferative disorders (PMID:15485920)
• findings indicate that ligation of retinol to a specific site embedded in the regulatory domain is an important feature of c-Raf regulation in the redox pathway. (PMID:15591313)
• proteomic analysis of Raf-1 signaling complexes was used to show that Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (MST2) (PMID:15618521)
• a novel Ras-independent ERK1/2 activation system in which p110gamma/Raf-1/MEK1/2 and PKA/B-Raf/MEK1/2 cooperate to activate ERK1/2. (PMID:15653554)
• The induction of the raf-1/MEK1 pathway blocks IGF-1-mediated intracellular neuroendocrine hormone regulation. This pathway may be a therapeutic target in gastrointestinal carcinoid tumor therapy. (PMID:15657590)
• Raf-1 may be involved in angiogenesis by controlling the expression of angiogenesis-related factors; study provides a possible strategy for the treatment of tumor angiogenesis by targeting Raf-1 (PMID:15662129)
• the HER2/Raf-1/AP-1 axis may promote the development of androgen insensitive prostate cancer, leading to early relapse (PMID:15666389)
• Role for caspase-9 mediated cleavage of Raf-1 in the negative feedback regulation of hematopoietic cell apoptosis induced by growth factor withdrawal. (PMID:15674327)
• regulated by an N-terminal autoinhibitory domain whose actions are blocked by interaction with Ras (PMID:15710605)
• essential role of Ras-induced conformational change in mitogen-activated protein kinase kinase activation by c-Raf (PMID:15711535)
• activation is regulated by CNK1 (PMID:15845549)
• Pak1-dependent Raf-1 phosphorylation regulates its mitochondrial localization, phosphorylation of BAD, and Bcl-2 association (PMID:15849194)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	raf1b	ENSDARG00000059406
danio_rerio	raf1a	ENSDARG00000096415
danio_rerio		ENSDARG00000102328
mus_musculus	Raf1	ENSMUSG00000000441
rattus_norvegicus	Raf1	ENSRNOG00000010153

Paralogs (23): MAP3K9 (ENSG00000006432), TESK2 (ENSG00000070759), MAP3K13 (ENSG00000073803), ARAF (ENSG00000078061), MAP3K20 (ENSG00000091436), RIPK2 (ENSG00000104312), LIMK1 (ENSG00000106683), TESK1 (ENSG00000107140), TNNI3K (ENSG00000116783), RIPK3 (ENSG00000129465), MAP3K10 (ENSG00000130758), RIPK1 (ENSG00000137275), MAP3K12 (ENSG00000139625), KSR1 (ENSG00000141068), MAP3K21 (ENSG00000143674), BRAF (ENSG00000157764), ILK (ENSG00000166333), MLKL (ENSG00000168404), KSR2 (ENSG00000171435), MOS (ENSG00000172680), MAP3K11 (ENSG00000173327), LIMK2 (ENSG00000182541), LRRK2 (ENSG00000188906)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:97847) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 99 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased body weight	3
decreased embryo size	3
enlarged heart	2
liver hypoplasia	2
decreased body length	2
cardiac hypertrophy	2
abnormal placenta labyrinth morphology	2
embryonic growth arrest	2
increased heart weight	2
cardiac fibrosis	2
increased cardiac output	2
embryonic growth retardation	2
increased myocardial fiber size	2
decreased cardiac muscle contractility	2
increased cardiac muscle contractility	2
increased apoptosis	2
abnormal placental labyrinth vasculature morphology	2
increased cardiac stroke volume	2
increased leukocyte cell number	1
increased neutrophil cell number	1
increased monocyte cell number	1
distended pericardium	1
small hair follicles	1
underdeveloped hair follicles	1
ruffled hair	1

+74 more (showing top 25).

Additional cross-species homologs

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

Organism	UniProt	Identity	Method
Coturnix japonica	P34908	100.0%	Diamond
Gallus gallus	Q04982	100.0%	Diamond
Pongo abelii	Q5R5M7	100.0%	Diamond
Bos taurus	A7E3S4	97.7%	Diamond
Sus scrofa	O19004	97.4%	Diamond
Caenorhabditis elegans	Q07292	92.4%	Diamond
Caenorhabditis briggsae	Q61UC4	92.4%	Diamond
Xenopus laevis	P09560	89.5%	Diamond
Ceratodon purpureus	P25848	89.4%	Diamond
Canis lupus familiaris	E2RSS3	89.2%	Diamond
Arabidopsis thaliana	Q8RWL6	80.2%	Diamond
Drosophila melanogaster	P11346	66.3%	Diamond
Plasmodium berghei ANKA	A0A509AH51	53.8%	Diamond
Dictyostelium discoideum	Q54XX5	53.3%	Diamond
Plasmodium falciparum 3D7	Q8IIT5	42.1%	Diamond
Avian retrovirus IC10	P10533	100.0%	Diamond
Rous-associated virus type 1	P27966	100.0%	Diamond
Avian carcinoma Mill Hill virus 2	P00531	98.9%	Diamond
Murine sarcoma virus 3611	P00532	98.8%	Diamond

Genomic neighbors (locus context)

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

Symbol	Type	Entrez
MKRN2	protein-coding	23609
TSEN2	protein-coding	80746
MKRN2OS	protein-coding	100129480
PPARG	protein-coding	5468
TMEM40	protein-coding	55287
CAND2	protein-coding	23066
RPL32	protein-coding	6161

Protein

Protein identifiers

RAF proto-oncogene serine/threonine-protein kinase — P04049 (reviewed: P04049)

Alternative names: Proto-oncogene c-RAF, Raf-1

All UniProt accessions (29): A0A0B4J1W9, A0A0S2Z4L5, A0A0S2Z559, A0A8I5KQ33, A0A8I5KQV4, A0A8I5KR46, A0A8I5KRD1, A0A8I5KS16, A0A8I5KSB0, A0A8I5KSI1, A0A8I5KSM4, A0A8I5KSV6, A0A8I5KT32, A0A8I5KTA5, A0A8I5KTK4, A0A8I5KUW4, A0A8I5KW44, A0A8I5KWA9, A0A8I5KWF7, A0A8I5KWS9, A0A8I5KX50, A0A8I5KYC4, A0A8I5KYP5, A0A8I5QJG5, A0A8I5QKU8, A0A8I5QKZ6, P04049, H7C155, L7RRS6

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at ‘Ser-75’. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation.

Subunit / interactions. Monomer. Homodimer. Heterodimerizes with BRAF and this heterodimer possesses a highly increased kinase activity compared to the respective homodimers or monomers. Heterodimerization is mitogen-regulated and enhanced by 14-3-3 proteins. MAPK1/ERK2 activation can induce a negative feedback that promotes the dissociation of the heterodimer. Forms a multiprotein complex with Ras (M-Ras/MRAS), SHOC2 and protein phosphatase 1 (PPP1CA, PPP1CB and PPP1CC). Interacts with LZTR1. Interacts with Ras proteins; the interaction is antagonized by RIN1. Weakly interacts with RIT1. Interacts (via N-terminus) with RGS14 (via RBD domains); the interaction mediates the formation of a ternary complex with BRAF, a ternary complex inhibited by GNAI1. Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23. Interacts with STK3/MST2; the interaction inhibits its pro-apoptotic activity. Interacts (when phosphorylated at Ser-259) with YWHAZ (unphosphorylated at ‘Thr-232’). Interacts with MAP2K1/MEK1 and MAP2K2/MEK2. Interacts with MAP3K5/ASF1 (via N-terminus) and this interaction inhibits the proapoptotic function of MAP3K5/ASK1. Interacts with PAK1 (via kinase domain). The phosphorylated form interacts with PIN1. The Ser-338 and Ser-339 phosphorylated form (by PAK1) interacts with BCL2. Interacts with PEBP1/RKIP and this interaction is enhanced if RAF1 is phosphorylated on residues Ser-338, Ser-339, Tyr-340 and Tyr-341. Interacts with ADCY2, ADCY5, ADCY6, DGKH, RCAN1/DSCR1, PPP1R12A, PKB/AKT1, PPP2CA, PPP2R1B, SPRY2, SPRY4, CNKSR1/CNK1, KSR2 and PHB/prohibitin. Interacts with ROCK2. In its active form, interacts with PRMT5. Interacts with FAM83B; displaces 14-3-3 proteins from RAF1 and activates RAF1. Interacts with PDE8A; the interaction promotes RAF1 activity. Interacts with MFHAS1. Interacts with GLS. Interacts with NEK10 and MAP2K1; the interaction is direct with NEK10 and required for ERK1/2-signaling pathway activation in response to UV irradiation.

Subcellular location. Cytoplasm. Cell membrane. Mitochondrion. Nucleus.

Tissue specificity. In skeletal muscle, isoform 1 is more abundant than isoform 2.

Post-translational modifications. Phosphorylation at Thr-269, Ser-338, Tyr-341, Thr-491 and Ser-494 results in its activation. Phosphorylation at Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2 results in its inactivation. Phosphorylation at Ser-259 induces the interaction with YWHAZ and inactivates kinase activity. Dephosphorylation of Ser-259 by the SHOC2-MRAS-PP1c (SMP) complex consisting of SHOC2, GTP-bound M-Ras/MRAS and the catalytic subunit of protein phosphatase 1 (PPP1CA, PPP1CB or PPP1CC); this relieves inactivation and stimulates kinase activity. Phosphorylation at Ser-338 by PAK1 and PAK5 and Ser-339 by PAK1 is required for its mitochondrial localization. Phosphorylation at Ser-621 in response to growth factor treatment stabilizes the protein, possibly by preventing proteasomal degradation. Phosphorylation at Ser-289, Ser-296, Ser-301, Ser-338 and Ser-621 are somehow linked to the methylation potential of cells. Treatment of cells with HGF in the presence of the methylation inhibitor 5’-methylthioadenosine (MTA) results in increased phosphorylation at Ser-338 and Ser-621 and decreased phosphorylation at Ser-296, Ser-301 and Ser-338. Dephosphorylation at Ser-338 by PPP5C results in an activity decrease. Methylated at Arg-563 in response to EGF treatment. This modification leads to destabilization of the protein, possibly through proteasomal degradation.

Disease relevance. Noonan syndrome 5 (NS5) [MIM:611553] 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. LEOPARD syndrome 2 (LPRD2) [MIM:611554] A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. The disease is caused by variants affecting the gene represented in this entry. Cardiomyopathy, dilated, 1NN (CMD1NN) [MIM:615916] A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Regulation is a highly complex process involving membrane recruitment, protein-protein interactions, dimerization, and phosphorylation/dephosphorylation events. Ras-GTP recruits RAF1 to the membrane, thereby promoting its activation. The inactive conformation of RAF1 is maintained by autoinhibitory interactions occurring between the N-terminal regulatory and the C-terminal catalytic domains and by the binding of a 14-3-3 protein that contacts two phosphorylation sites, Ser-259 and Ser-621. Upon mitogenic stimulation, Ras and PPP2R1A cooperate to release autoinhibition and the subsequent phosphorylation of activating sites: Ser-338, Tyr-341, Thr-491, and Ser-494, yields a fully active kinase. Through a negative feedback mechanism involving MAPK1/ERK2, RAF1 is phosphorylated on Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2, which yields an inactive, desensitized kinase. The signaling-competent conformation of RAF1 is finally re-established by the coordinated action of PIN1, a prolyl isomerase that converts pSer and pThr residues from the cis to the trans conformation, which is preferentially recognized and dephosphorylated by PPP2R1A. Activated by homodimerization and heterodimerization (with BRAF). Also regulated through association with other proteins such as KSR2, CNKSR1/CNK1, PEBP1/RKIP, PHB/prohibitin and SPRY4. PEBP1/RKIP acts by dissociating RAF1 from its substrates MAP2K1/MEK1 and MAP2K2/MEK2. PHB/prohibitin facilitates the displacement of 14-3-3 from RAF1 by activated Ras, thereby promoting cell membrane localization and phosphorylation of RAF1 at the activating Ser-338. SPRY4 inhibits Ras-independent, but not Ras-dependent, activation of RAF1. CNKSR1/CNK1 regulates Src-mediated RAF1 activation.

Cofactor. Binds 2 Zn(2+) ions per subunit.

Similarity. Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. RAF subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P04049-1	1, 6C	yes
P04049-2	2, 1A

RefSeq proteins (8): NP_001341618, NP_001341619, NP_001341620, NP_001341621, NP_001341622, NP_001341623, NP_001341624, NP_002871* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR002219	PKC_DAG/PE	Domain
IPR003116	RBD_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020454	DAG/PE-bd	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR046349	C1-like_sf	Homologous_superfamily
IPR051681	Ser/Thr_Kinases-Pseudokinases	Family

Pfam: PF00130, PF02196, PF07714

Enzyme classification (BRENDA)

• EC 2.7.10.2 — non-specific protein-tyrosine kinase (BRENDA: 41 organisms, 396 substrates, 479 inhibitors, 43 Km, 32 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.014–17.64	12
[KDSRC KINASE]-L-TYROSINE	0.0057–0.24	12
POLY(GLU4-TYR)	0.018–0.659	10
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO	0.057	1
S1 PEPTIDE	0.037	1
EEEEY	—	0

Catalyzed reactions (Rhea)

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (130 total): strand 26, sequence variant 24, helix 23, modified residue 20, binding site 10, turn 7, mutagenesis site 7, compositionally biased region 3, domain 2, region of interest 2, sequence conflict 2, chain 1, zinc finger region 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

showing 30 of 76 structures by resolution:

PDB	Title	Method	Resolution (Å)
3IQU	Crystal Structure of human 14-3-3 sigma in Complex with Raf1 peptide (6mer)	X-RAY DIFFRACTION	1.05
3IQJ	Crystal Structure of human 14-3-3 sigma in Complex with Raf1 peptide (10mer)	X-RAY DIFFRACTION	1.15
3IQV	Crystal Structure of human 14-3-3 sigma in Complex with Raf1 peptide (6mer) and …	X-RAY DIFFRACTION	1.2
6VJJ	Crystal Structure of wild-type KRAS4b (GMPPNP-bound) in complex with RAS-binding domain …	X-RAY DIFFRACTION	1.4
8ATS	Small molecular stabilizer for C-RAF (pS259) and 14-3-3 (1075306)	X-RAY DIFFRACTION	1.4
9EW1	Ternary structure of 14-3-3s, CRAF phosphopeptide (pS259) and compound 79 (1124379).	X-RAY DIFFRACTION	1.4
9EW3	Ternary structure of 14-3-3s, C-RAF phosphopeptide 12-mer (pS259) and compound 78 …	X-RAY DIFFRACTION	1.4
8AV0	small molecule stabilizer (compound 1) for C-RAF pS259 and 14-3-3	X-RAY DIFFRACTION	1.5
9EW5	Ternary structure of 14-3-3s, C-RAF phosphopeptide (pS259) 12mer and compound 23 (1083848)	X-RAY DIFFRACTION	1.5
9S2J	Ternary structure of 14-3-3s, CRAF S257L NS mutant phosphopeptide (pS259) and compound 78 …	X-RAY DIFFRACTION	1.5
9S2P	Ternary structure of 14-3-3s, CRAF V263A NS mutant phosphopeptide (pS259), and compound …	X-RAY DIFFRACTION	1.5
8A68	Small molecule stabilizer (compound 5) for C-RAF(pS259) and 14-3-3	X-RAY DIFFRACTION	1.6
8A6F	Small molecule stabilizer (compound 8) for C-RAF and 14-3-3	X-RAY DIFFRACTION	1.6
8A6H	Small molecule stabilizer (compound 7) for C-RAF and 14-3-3	X-RAY DIFFRACTION	1.6
9EW4	Ternary structure of 14-3-3s, C-RAF phosphopeptide 12mer (pS259) and compound 86 (1124384)	X-RAY DIFFRACTION	1.6
8JNB	CRAF ras-binding domain chimera, ligand complex	X-RAY DIFFRACTION	1.62
8T74	Crystal structure of KRAS4a (GMPPNP) in complex with RAF1 (RBD)	X-RAY DIFFRACTION	1.65
9S2I	Ternary structure of 14-3-3, CRAF R256S NS mutant phosphopeptide (pS259), and compound 78 …	X-RAY DIFFRACTION	1.67
9YGS	Crystal structure of GMPPNP bound KRAS-Y71H in complex with RBD domain of CRAF(RAF1)	X-RAY DIFFRACTION	1.68
4IEA	14-3-3 isoform sigma in complex with a phosphorylated C-RAF peptide	X-RAY DIFFRACTION	1.7
8ATR	Small molecular stabilizer for C-RAF (pS259) and 14-3-3 (1075297)	X-RAY DIFFRACTION	1.7
8JNA	CRAF ras-binding domain chimera, apo form	X-RAY DIFFRACTION	1.7
8S42	Ternary structure of 14-3-3s, C-RAF phosphopeptide (pS259) and compound 80 (1124898)	X-RAY DIFFRACTION	1.7
9EW7	Binary structure of 14-3-3s and CRAF phosphopeptide (pS259)	X-RAY DIFFRACTION	1.8
9S2O	Ternary structure of 14-3-3s, CRAF R256S NS mutant phosphopeptide (pS259), and compound …	X-RAY DIFFRACTION	1.8
9S2L	Ternary structure of 14-3-3s, CRAF R256S NS mutant phosphopeptide (pS259), and compound …	X-RAY DIFFRACTION	1.85
9S2N	Ternary structure of 14-3-3s, CRAF V263A NS mutant phosphopeptide (pS259), and compound …	X-RAY DIFFRACTION	1.85
1C1Y	CRYSTAL STRUCTURE OF RAP.GMPPNP IN COMPLEX WITH THE RAS-BINDING-DOMAIN OF C-RAF1 KINASE …	X-RAY DIFFRACTION	1.9
3KUC	Complex of Rap1A(E30D/K31E)GDP with RafRBD(A85K/N71R)	X-RAY DIFFRACTION	1.92
4FJ3	14-3-3 isoform zeta in complex with a diphoyphorylated C-RAF peptide	X-RAY DIFFRACTION	1.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04049-F1	68.24	0.30

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, TKL Ser/Thr protein kinases, Predicted intracellular proteins, RAS pathway related proteins, Cancer-related genes, Candidate cancer biomarkers, Disease related genes, FDA approved drug targets, Small molecule drugs, Human disease related genes, Congenital malformations, Other congenital malformations

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; plasma membrane

Antibody reliability (HPA): IH approved · IF supported

Functional residue map

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

Catalytic / active sites (1)

Position	Role
468	proton acceptor

Ligand- & substrate-binding residues (10)

Position	Role
139	Zn(2+)
152	Zn(2+)
155	Zn(2+)
165	Zn(2+)
168	Zn(2+)
173	Zn(2+)
176	Zn(2+)
184	Zn(2+)
355–363	ATP
375	ATP

Post-translational modifications (20)

Type	Positions
Phosphoserine	29, 43, 252, 259, 289, 296, 301, 338, 339, 471, 494, 499, 621, 642
Phosphothreonine	268, 269, 491
Phosphotyrosine	340, 341
Symmetric dimethylarginine	563

Mutagenesis-validated functional residues (7)

Position	Phenotype
338–339	reduced kinase activity; when associated with 340-d-d-341.
338–339	non-inhibited by ppp5c. constitutively active and non-inhibited by ppp5c; when associated with 340-d-d-341.
340–341	constitutively active and highly phosphorylated on s-338, inhibited by ppp5c. reduced kinase activity; when associated with 338-a-a-339 …
375	catalytically inactive.
491	increased kinase activity but can still be inhibited by ppp5c; when associated with d-494.
494	increased kinase activity but can still be inhibited by ppp5c; when associated with d-491.
563	loss of methylation. increased stability and catalytic activity in response to egf treatment.

Function

Pathways and Gene Ontology

Reactome pathways

17 curated (TAS) of 37; 13 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

37 pathways:

ID	Pathway	Evidence
R-HSA-9726842	Gain-of-function MRAS complexes activate RAF signaling ⚕	curated
R-HSA-6802955	Paradoxical activation of RAF signaling by kinase inactive BRAF ⚕	curated
R-HSA-9726840	SHOC2 M1731 mutant abolishes MRAS complex function ⚕	curated
R-HSA-6802952	Signaling by BRAF and RAF1 fusions ⚕	curated
R-HSA-9656223	Signaling by RAF1 mutants ⚕	curated
R-HSA-6802948	Signaling by high-kinase activity BRAF mutants ⚕	curated
R-HSA-6802946	Signaling by moderate kinase activity BRAF mutants ⚕	curated
R-HSA-9649948	Signaling downstream of RAS mutants ⚕	curated
R-HSA-5621575	CD209 (DC-SIGN) signaling	curated
R-HSA-430116	GP1b-IX-V activation signalling	curated
R-HSA-9732724	IFNG signaling activates MAPKs	curated
R-HSA-5674135	MAP2K and MAPK activation	curated
R-HSA-5674499	Negative feedback regulation of MAPK pathway	curated
R-HSA-5675221	Negative regulation of MAPK pathway	curated
R-HSA-5673000	RAF activation	curated
R-HSA-392517	Rap1 signalling	curated
R-HSA-2672351	Stimuli-sensing channels	curated
R-HSA-1643685	Disease ⚕	—
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers ⚕	—
R-HSA-6802957	Oncogenic MAPK signaling ⚕	—
R-HSA-9660537	Signaling by MRAS-complex mutants ⚕	—
R-HSA-6802949	Signaling by RAS mutants ⚕	—
R-HSA-1280218	Adaptive Immune System	—
R-HSA-5621481	C-type lectin receptors (CLRs)	—
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-109582	Hemostasis	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-913531	Interferon Signaling	—
R-HSA-877300	Interferon gamma signaling	—
R-HSA-983712	Ion channel transport	—
R-HSA-5683057	MAPK family signaling cascades	—
R-HSA-5684996	MAPK1/MAPK3 signaling	—
R-HSA-76002	Platelet activation, signaling and aggregation	—
R-HSA-5673001	RAF/MAP kinase cascade	—
R-HSA-162582	Signal Transduction	—
R-HSA-382551	Transport of small molecules	—

MSigDB gene sets: 932 (showing top): PID_BCR_5PATHWAY, PID_SHP2_PATHWAY, GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, BIOCARTA_FMLP_PATHWAY, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_RESPONSE_TO_MUSCLE_STRETCH, BIOCARTA_MAL_PATHWAY, GOBP_REGULATION_OF_PHOSPHORYLATION

GO Biological Process (21): MAPK cascade (GO:0000165), protein phosphorylation (GO:0006468), apoptotic process (GO:0006915), signal transduction (GO:0007165), neuromuscular junction development (GO:0007528), negative regulation of cell population proliferation (GO:0008285), insulin receptor signaling pathway (GO:0008286), Schwann cell development (GO:0014044), negative regulation of protein-containing complex assembly (GO:0031333), positive regulation of peptidyl-serine phosphorylation (GO:0033138), regulation of Rho protein signal transduction (GO:0035023), ERBB2-ERBB3 signaling pathway (GO:0038133), wound healing (GO:0042060), myelination (GO:0042552), regulation of apoptotic process (GO:0042981), negative regulation of apoptotic process (GO:0043066), positive regulation of MAPK cascade (GO:0043410), regulation of cell differentiation (GO:0045595), insulin-like growth factor receptor signaling pathway (GO:0048009), type II interferon-mediated signaling pathway (GO:0060333), ERBB signaling pathway (GO:0038127)

GO Molecular Function (15): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), MAP kinase kinase kinase activity (GO:0004709), ATP binding (GO:0005524), zinc ion binding (GO:0008270), adenylate cyclase activator activity (GO:0010856), enzyme binding (GO:0019899), identical protein binding (GO:0042802), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), small GTPase binding (GO:0031267), metal ion binding (GO:0046872)

GO Cellular Component (8): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), pseudopodium (GO:0031143)

Reactome top-level categories

11 top-level categories:

Category	Pathways
Oncogenic MAPK signaling	5
RAF/MAP kinase cascade	3
Signaling by MRAS-complex mutants	2
Immune System	2
Ion channel transport	1
Adaptive Immune System	1
Platelet activation, signaling and aggregation	1
C-type lectin receptors (CLRs)	1
Negative regulation of MAPK pathway	1
Signaling by RAS mutants	1
Interferon gamma signaling	1

GO top-level categories

showing 60 of 73 GO namespaces:

Category	Terms
intracellular membrane-bounded organelle	3
cytoplasm	3
regulation of cellular process	2
cell surface receptor protein tyrosine kinase signaling pathway	2
apoptotic process	2
MAPK cascade	2
protein kinase activity	2
protein binding	2
cellular anatomical structure	2
intracellular signaling cassette	1
phosphorylation	1
protein modification process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
cellular response to stimulus	1
synapse organization	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cellular response to insulin stimulus	1
Schwann cell differentiation	1
glial cell development	1
regulation of protein-containing complex assembly	1
negative regulation of cellular component organization	1
protein-containing complex assembly	1
positive regulation of protein phosphorylation	1
peptidyl-serine phosphorylation	1
regulation of peptidyl-serine phosphorylation	1
Rho protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
ERBB2 signaling pathway	1
ERBB3 signaling pathway	1
response to wounding	1
tissue regeneration	1
axon ensheathment	1
regulation of programmed cell death	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
cell differentiation	1
regulation of developmental process	1
cellular response to type II interferon	1
interferon-mediated signaling pathway	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
protein serine/threonine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
transition metal ion binding	1
adenylate cyclase activity	1
cyclase activator activity	1
adenylate cyclase regulator activity	1
nucleoside phosphate binding	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 14 of 44 annotations. The rest are phylogenetic / computational / electronic (IEA).

14 experimentally-supported GO terms:

GO term	NS	Evidence
negative regulation of apoptotic process	BP	direct assay
negative regulation of cell population proliferation	BP	direct assay
negative regulation of protein-containing complex assembly	BP	direct assay
positive regulation of MAPK cascade	BP	direct assay
positive regulation of peptidyl-serine phosphorylation	BP	direct assay
Golgi apparatus	CC	physical interaction
cytoplasm	CC	direct assay
cytosol	CC	direct assay
plasma membrane	CC	direct assay
adenylate cyclase activator activity	MF	direct assay
enzyme binding	MF	physical interaction
identical protein binding	MF	physical interaction
protein kinase activity	MF	experiment
protein serine/threonine kinase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 3,422 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAF1	PEBP1	P30086	814
RAF1	HRAS	P01112	813
RAF1	SOS1	Q07889	783
RAF1	GRB2	P29354	756
RAF1	NRAS	P01111	744
RAF1	KRAS	P01116	740
RAF1	MAP2K1	Q02750	710
RAF1	BRAF	P15056	708
RAF1	MRAS	O14807	706
RAF1	JUN	P05412	693
RAF1	SPRED1	Q7Z699	682
RAF1	LAMTOR3	Q9UHA4	678
RAF1	PIK3CA	P42336	677
RAF1	PTPN11	Q06124	671
RAF1	RALA	P11233	668

IntAct

Human interaction partners of RAF1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 118 partners by confidence:

Partner	Interaction type	MIscore	Records
HRAS	physical association	0.980	28
BRAF	direct interaction	0.970	57
YWHAZ	direct interaction	0.970	15
MAP2K1	association	0.960	32
YWHAB	association	0.960	15
YWHAH	physical association	0.940	2
NRAS	physical association	0.930	9
YWHAQ	association	0.930	3
YWHAG	association	0.930	2
YWHAE	physical association	0.920	5
CDC37	physical association	0.900	1
SFN	direct interaction	0.890	6
HSP90AB1	physical association	0.860	3
MAP2K2	physical association	0.850	4
PEBP1	physical association	0.760	10
KRAS	direct interaction	0.750	7
TIMM50	physical association	0.740	3
HSP90AA1	physical association	0.740	1
BAG2	physical association	0.670	1
CCT3	physical association	0.660	3
STK3	physical association	0.650	6
EGFR	physical association	0.650	3
CALU	association	0.640	3
ARAF	association	0.640	2
AKT1	proximity	0.620	3
RAP1A	direct interaction	0.620	2
PEBP4	physical association	0.600	3
HSPA5	physical association	0.580	5
PAQR3	physical association	0.580	2
NS5A	physical association	0.560	4

BioGRID (2,445 interactions; top human partners by supporting records in a sample of 600 records): HRAS (Affinity Capture-Western; 34 records), KRAS (Affinity Capture-MS; 15 records), YWHAZ (Affinity Capture-MS; 14 records), MAP2K1 (Affinity Capture-Western; 13 records), YWHAB (Affinity Capture-MS; 12 records), BRAF (Affinity Capture-MS; 11 records), CDC37 (Affinity Capture-MS; 10 records), HSP90AA1 (Affinity Capture-Western; 10 records), YWHAH (Affinity Capture-MS; 10 records), YWHAQ (Reconstituted Complex; 10 records), YWHAG (Affinity Capture-MS; 9 records), NRAS (Synthetic Lethality; 8 records), GRB10 (Co-fractionation; 7 records), YWHAE (Affinity Capture-MS; 7 records), PEBP1 (Affinity Capture-Western; 6 records)

SIGNOR signaling

showing 50 of 112 signaling interactions:

A	Effect	B	Mechanism
2-chloro-5-(2-phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)phenol	down-regulates	RAF1	“chemical inhibition”
RAF1	down-regulates	MAP3K5	binding
PKN1	up-regulates	RAF1	phosphorylation
CNKSR2	up-regulates	RAF1	binding
WDR83	up-regulates	RAF1	binding
RAF1	down-regulates	STK3	binding
MAPK3	down-regulates	RAF1	phosphorylation
CNKSR1	up-regulates	RAF1	binding
PPP2CA	up-regulates	RAF1	dephosphorylation
KRAS	up-regulates	RAF1	binding
AKT1	down-regulates	RAF1	phosphorylation
RAF1	down-regulates	BAD	phosphorylation
sorafenib	down-regulates	RAF1	“chemical inhibition”
NRAS	up-regulates	RAF1	relocalization
PAK1	up-regulates	RAF1	phosphorylation
3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[(3-methyl-4-oxo-6-quinazolinyl)amino]phenyl]benzamide	down-regulates	RAF1	“chemical inhibition”
RAF1	down-regulates	STK4	binding
4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide	down-regulates	RAF1	“chemical inhibition”
1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine	down-regulates	RAF1	“chemical inhibition”
“Raf265 derivative”	down-regulates	RAF1	“chemical inhibition”
regorafenib	down-regulates	RAF1	“chemical inhibition”
“ZM 336372”	down-regulates	RAF1	“chemical inhibition”
AMPK	down-regulates	RAF1	phosphorylation
AMPK	up-regulates	RAF1	phosphorylation
AKT2	“down-regulates activity”	RAF1	phosphorylation
HRAS	up-regulates	RAF1	binding
RAF1	“up-regulates activity”	MAP2K1	phosphorylation
PPP2R2A	“up-regulates activity”	RAF1	binding
PPP2R5D	“up-regulates activity”	RAF1	binding
PP2CA_R1A_R2A	“up-regulates activity”	RAF1	dephosphorylation
PP2Ca_R1A_Bd	“up-regulates activity”	RAF1	dephosphorylation
AKT	down-regulates	RAF1	phosphorylation
ERK1/2	down-regulates	RAF1	phosphorylation
RAF1	“up-regulates activity”	MEK1/2	phosphorylation
RAF1	up-regulates	MEK1/2	phosphorylation
PPP1CA	“up-regulates activity”	RAF1	dephosphorylation
SPRY4	“down-regulates activity”	RAF1	binding
RAF1	up-regulates	MAP2K2	phosphorylation
RAF1	down-regulates	STK3/4	binding
Gbeta	down-regulates	RAF1	phosphorylation
HECTD3	“down-regulates quantity by destabilization”	RAF1	polyubiquitination
KSR2	“up-regulates activity”	RAF1	binding
KSR1	“up-regulates activity”	RAF1	binding
RAF1	“down-regulates quantity by destabilization”	KLF10	phosphorylation
PLK1	“up-regulates activity”	RAF1	phosphorylation
PAK6	“up-regulates activity”	RAF1	phosphorylation
RAF1	“down-regulates activity”	PPP1R12A	phosphorylation
RAF1	“up-regulates activity”	XIAP	phosphorylation
RAF1	“down-regulates activity”	RB1	phosphorylation
MAP2K1	“up-regulates activity”	RAF1	phosphorylation

Protein complexes (CORUM) (17)

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

17 complexes by size:

Complex	Subunits	Members
★ BRAF-KSR1-MAP2K1-RAF1-YWHAE complex	5	RAF1, YWHAE, BRAF, KSR1, MAP2K1
★ CDC37-HSP90AB1-RAF1 complex	3	CDC37, HSP90AB1, RAF1
★ GNG2-RACK1-RAF1 complex	3	GNG2, RACK1, RAF1
★ MAP2K1-RAF1-YWHAE complex	3	MAP2K1, RAF1, YWHAE
★ BRAF-RAF1-YWHAZ complex	3	YWHAZ, BRAF, RAF1
★ KSR1-RAF1-MAP2K1 complex	3	KSR1, MAP2K1, RAF1
★ CNK1-SRC-RAF1 complex	3	CNKSR1, RAF1, SRC
★ AURKA-HRAS-RAF1 complex	3	HRAS, RAF1, AURKA
★ MAP2K1-NEK10-RAF1 complex	3	MAP2K1, NEK10, RAF1
★ PAK1-RAF1 complex	2	PAK1, RAF1
★ MITF -RAF1 complex	2	MITF, RAF1
★ MAP2K1-RAF1 complex	2	MAP2K1, RAF1
★ HERC1-RAF1 complex	2	RAF1, HERC1
★ HRAS-RAF1 complex	2	HRAS, RAF1
★ BRAF-RAF1 complex, RAS stimulated	2	BRAF, RAF1
★ RAF1-CNK1 complex, RAS stimulated	2	RAF1, CNKSR1
★ RAF1 homodimer	1	RAF1

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 118 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
Activation of BAD and translocation to mitochondria	9	69.2×	2e-13
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	54.3×	3e-11
Activation of BH3-only proteins	10	50.1×	2e-13
RAF activation	14	47.5×	3e-18
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	47.5×	3e-09
Constitutive Signaling by EGFRvIII	6	43.3×	1e-07
Signaling by ERBB2 ECD mutants	6	40.7×	1e-07
Negative regulation of MAPK pathway	15	40.2×	3e-18

GO biological processes:

GO term	Partners	Fold	FDR
hepatocyte apoptotic process	5	47.0×	1e-05
response to lead ion	5	41.8×	2e-05
release of cytochrome c from mitochondria	5	31.4×	7e-05
protein targeting	6	19.6×	8e-05
Ras protein signal transduction	9	16.5×	1e-06
substantia nigra development	5	16.4×	1e-03
MAPK cascade	11	15.1×	1e-07
ERK1 and ERK2 cascade	5	14.2×	2e-03

Disease & clinical

Genetic variants

Variant evidence for RAF1: 1,408 ClinVar records (40 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

1,408 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	27
Uncertain significance	664
Likely benign	493
Benign	73

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 40 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
13957	NM_002880.4(RAF1):c.770C>T (p.Ser257Leu)	Pathogenic	reviewed by expert panel	48
13958	NM_002880.4(RAF1):c.781C>T (p.Pro261Ser)	Pathogenic	reviewed by expert panel	16
13960	NM_002880.4(RAF1):c.1837C>G (p.Leu613Val)	Pathogenic	reviewed by expert panel	13
40601	NM_002880.4(RAF1):c.775T>A (p.Ser259Thr)	Pathogenic	reviewed by expert panel	10
40613	NM_002880.4(RAF1):c.1082G>C (p.Gly361Ala)	Pathogenic	reviewed by expert panel	9
21342	NM_002880.4(RAF1):c.1472C>T (p.Thr491Ile)	Pathogenic	reviewed by expert panel	7
44633	NM_002880.4(RAF1):c.776C>A (p.Ser259Tyr)	Pathogenic	reviewed by expert panel	7
504514	NM_002880.4(RAF1):c.775T>G (p.Ser259Ala)	Pathogenic	reviewed by expert panel	5
40599	NM_002880.4(RAF1):c.768G>T (p.Arg256Ser)	Likely pathogenic	reviewed by expert panel	7
40607	NM_002880.4(RAF1):c.788T>G (p.Val263Gly)	Likely pathogenic	reviewed by expert panel	7
40600	NM_002880.4(RAF1):c.769T>C (p.Ser257Pro)	Likely pathogenic	reviewed by expert panel	4
40603	NM_002880.4(RAF1):c.776C>T (p.Ser259Phe)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
426303	NM_002880.4(RAF1):c.778A>C (p.Thr260Pro)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
2883997	NM_002880.4(RAF1):c.786T>G (p.Asn262Lys)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
13959	NM_002880.4(RAF1):c.1472C>G (p.Thr491Arg)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3

Per-variant reference — Sugi Variant

Explore RAF1’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

AlphaMissense

2,233 missense substitutions predicted likely pathogenic (of 4,290 scored), across 450 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M409	9	0.982	0.999
M512	9	0.974	0.998
M456	9	0.939	0.999
H173	8	1.000	1.000
D486	8	1.000	1.000
H139	8	0.999	1.000
H402	8	0.999	1.000
H460	8	0.999	1.000
D468	8	0.999	1.000
D530	8	0.999	1.000
F408	8	0.998	1.000
H466	8	0.998	1.000
F487	8	0.998	1.000
F390	8	0.996	1.000
F475	8	0.995	1.000
F599	8	0.994	0.999
F172	8	0.993	1.000
H434	8	0.987	0.999
F163	8	0.986	1.000
H369	8	0.986	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.76e-05
Glioblastoma Multiforme (validation)	favorable	3.08e-05
Kidney Chromophobe (TCGA)	unfavorable	0.000406

Disease associations

OMIM: gene MIM:164760 | disease phenotypes: MIM:611553, MIM:611554, MIM:615916, MIM:163950, MIM:151100, MIM:192600, MIM:609942

GenCC curated gene-disease

8 curated gene-disease records:

Disease	Classification	Inheritance	Records
Noonan syndrome 5	Definitive	Autosomal dominant	5
Noonan syndrome	Definitive	Autosomal dominant	2
dilated cardiomyopathy 1NN	Strong	Autosomal dominant	3
LEOPARD syndrome 2	Strong	Autosomal dominant	3
Noonan syndrome with multiple lentigines	Supportive	Autosomal dominant	2
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant
Costello syndrome	Disputed Evidence	Autosomal dominant
cardiofaciocutaneous syndrome	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity

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

4 validity classifications:

Disease	Classification	Inheritance
Costello syndrome	Disputed	AD
Noonan syndrome	Definitive	AD
cardiofaciocutaneous syndrome	Disputed	AD
Noonan syndrome with multiple lentigines	Limited	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (18 panels, 18 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

18 panels:

Panel	Rating
Adult solid tumours cancer susceptibility	green
Childhood solid tumours	green
Childhood solid tumours cancer susceptibility	green
DDG2P	green
Fetal anomalies	green
Fetal hydrops	green
Hypotonic infant	green
IUGR and IGF abnormalities	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Monogenic short stature	green
Neurofibromatosis Type 1	green
Paediatric disorders	green
Paediatric or syndromic cardiomyopathy	green
Pigmentary skin disorders	green
Primary lymphoedema	green
RASopathies	green
Unexplained death in infancy and sudden unexplained death in childhood	green

Mondo (13): Noonan syndrome 5 (MONDO:0012690), LEOPARD syndrome 2 (MONDO:0012691), dilated cardiomyopathy 1NN (MONDO:0014396), Noonan syndrome (MONDO:0018997), RASopathy (MONDO:0021060), Noonan syndrome with multiple lentigines (MONDO:0007893), Noonan syndrome 1 (MONDO:0008104), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), hypertrophic cardiomyopathy 1 (MONDO:0008647), Noonan syndrome 3 (MONDO:0012371), Costello syndrome (MONDO:0009026), cardiofaciocutaneous syndrome (MONDO:0015280), (MONDO:0015470)

Orphanet (5): Familial isolated dilated cardiomyopathy (Orphanet:154), Noonan syndrome with multiple lentigines (Orphanet:500), RASopathy (Orphanet:536391), Noonan syndrome (Orphanet:648), Noonan syndrome and Noonan-related syndrome (Orphanet:98733)

MeSH disease descriptors

8 disease descriptors:

Descriptor	Name	Tree numbers
D056685	Costello Syndrome	C05.660.207.219; C16.131.077.256; C16.320.188
D044542	LEOPARD Syndrome	C05.660.207.525; C14.240.400.695; C14.280.400.695; C14.280.484.716.525; C16.131.077.525; C16.131.240.400.685; C16.131.621.207.525; C17.800.621.430.530.550.525
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
C535579	Cardiofaciocutaneous syndrome *(supp.)*
C537117	LEOPARD syndrome, 2 *(supp.)*
C548083	Noonan Syndrome 5 *(supp.)*
C537846	Noonan like syndrome *(supp.)*
C537847	Noonan syndrome 3 *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (8): CHEMBL1906 (SINGLE PROTEIN), CHEMBL2111351 (PROTEIN FAMILY), CHEMBL3559685 (PROTEIN FAMILY), CHEMBL3883317 (PROTEIN FAMILY), CHEMBL3885566 (PROTEIN FAMILY), CHEMBL4106189 (PROTEIN COMPLEX), CHEMBL5291962 (PROTEIN COMPLEX), CHEMBL5291977 (PROTEIN-PROTEIN INTERACTION)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the RAF1 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

7 curated-mechanism drugs:

Drug	Modality	Max phase
REGORAFENIB	Small molecule	4
SORAFENIB TOSYLATE	Small molecule	4
XL-281	Small molecule	2
ARQ-736	Small molecule	1
LGX-806	Unknown	1
LY-3009120	Small molecule	1
RG-7376	Unknown	1

Drugs acting on a complex or family that includes this protein

Curated ChEMBL mechanism-of-action drugs whose target is a protein complex or family of ≤10 members that includes RAF1 — the drug acts on the assembly or class, not necessarily on this subunit alone.

3 drugs via a complex or family:

Drug	Target (ChEMBL)	Members	Max phase
TOVORAFENIB	RAF serine/threonine protein kinase	3	4
NAPORAFENIB	B-raf/RAF proto-oncogene serine/threonine-protein kinase	2	3
BELVARAFENIB	RAF serine/threonine protein kinase	3	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 427,407 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

31 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1946170	REGORAFENIB	4	13,318
CHEMBL1336	SORAFENIB	4	87,476
CHEMBL2028663	DABRAFENIB	4	13,060
CHEMBL5416410	DASATINIB	4	674
CHEMBL553	ERLOTINIB	4	109,860
CHEMBL941	IMATINIB	4	113,105
CHEMBL255863	NILOTINIB	4	39,362
CHEMBL477772	PAZOPANIB	4	16,241
CHEMBL3348923	TOVORAFENIB	4	879
CHEMBL1229517	VEMURAFENIB	4	16,487
CHEMBL3264002	AVUTOMETINIB	3	2,320
CHEMBL572881	MOTESANIB	3	4,820
CHEMBL4583691	NAPORAFENIB	3	1,253
CHEMBL1096380	PLINABULIN	3	713
CHEMBL3977543	BELVARAFENIB	2	718
CHEMBL5800160	BRIMARAFENIB	2	33
CHEMBL2029988	CEP-32496	2	1,196
CHEMBL105442	CI-1040	2	4,094
CHEMBL103667	DORAMAPIMOD	2	1,746
CHEMBL5095099	EXARAFENIB	2	52
CHEMBL1230609	FORETINIB	2
CHEMBL475251	R-406	2
CHEMBL558752	RAF-265	2
CHEMBL1738757	REBASTINIB	2
CHEMBL4800252	RISOVALISIB	2
CHEMBL1790006	TOLONIUM CHLORIDE	2
CHEMBL3577124	LY-3009120	1
CHEMBL574738	AST-487	1
CHEMBL1614710	OSI-930	1
CHEMBL295316	PLUMBAGIN	1
CHEMBL4212692	XP-102	1

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — RAF family

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

Ligand	Action	Affinity	Parameter
brimarafenib	Inhibition	9.72	pIC50
TAK-632	Inhibition	8.85	pIC50
L779450	Inhibition	8.85	pIC50
SB590885	Inhibition	8.76	pIC50
XP-102	Binding	8.52	pKd
naporafenib	Inhibition	8.44	pKd
tinlorafenib	Inhibition	8.39	pIC50
belvarafenib	Inhibition	8.3	pIC50
sorafenib	Inhibition	8.22	pIC50
CCT241161	Inhibition	8.22	pIC50
mosperafenib	Inhibition	8.05	pKd
GW5074	Inhibition	8.05	pIC50
exarafenib	Inhibition	8.0	pIC50
CCT196969	Inhibition	8.0	pIC50
RIPK3 inhibitor 18	Inhibition	7.96	pIC50
LY3009120	Inhibition	7.82	pIC50
plixorafenib	Inhibition	7.64	pIC50
ZM336372	Inhibition	7.51	pIC50
NST-628	Binding	7.41	pKd
agerafenib	Inhibition	7.41	pKd
OSI-930	Inhibition	7.39	pIC50
vemurafenib	Inhibition	7.32	pIC50
avutometinib	Inhibition	7.25	pIC50
balamapimod	Inhibition	6.94	pIC50

Binding affinities (BindingDB)

3620 measured of 5177 human assays (5401 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(rac)-N-(3-(1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide	IC50	0.001 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
(rac)-N-(3-(6-hydroxy-6-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide	IC50	0.002 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[4-methyl-3-(6-oxo-2,4,4a,5-tetrahydro-1H-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	0.002 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl]-5-(trifluoromethyl)pyridine-3-carboxamide	IC50	0.002 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl]-4-(trifluoromethyl)pyridine-2-carboxamide	IC50	0.003 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
2-(2-fluoropropan-2-yl)-N-[3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl]pyridine-4-carboxamide	IC50	0.004 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
(trans)-2-(1,1-difluoroethyl)-N-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide	IC50	0.005 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-(6,6-difluoro-2,4,4a,5-tetrahydro-1H-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	0.005 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
2-(1,1-Difluoroethyl)-N-(3-((4aR,5R)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide and 2-(1,1-difluoroethyl)-N-(3-((4aS,5S)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide	IC50	0.005 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
rac-trans-N-(3-(5-(Hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide and rac-cis-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide	IC50	0.005 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-(4-methyl-3-spiro[2,4,4a,6-tetrahydro-1H-[1,4]oxazino[4,3-a][1,5]naphthyridine-5,3’-oxetane]-9-ylphenyl)-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	0.005 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
(trans)-N-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide	IC50	0.006 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-(3-(5,5-bis(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(1,1-difluoroethyl)isonicotinamide	IC50	0.006 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
2-(1,1-difluoroethyl)-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide	IC50	0.006 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-[(4aS,6S)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl]-4-methylphenyl]-2-(1,1-difluoroethyl)pyridine-4-carboxamide	IC50	0.006 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
3-(2-cyanopropan-2-yl)-N-[5-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-6-methyl-3-pyridinyl]benzamide	IC50	0.007 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-[5,5-bis(hydroxymethyl)-2,4,4a,6-tetrahydro-1H-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl]-4-methylphenyl]-4-(trifluoromethyl)pyridine-2-carboxamide	IC50	0.007 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
(trans)-N-(3-(6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide	IC50	0.008 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
(rac)-(cis)-N-(3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide	IC50	0.008 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[5-(6-hydroxy-6-methyl-2,4,4a,5-tetrahydro-1H-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-6-methyl-3-pyridinyl]-3-(trifluoromethyl)benzamide	IC50	0.008 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-(8-ethyl-9-oxo-12-oxa-1,6,8-triazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-trien-4-yl)-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	0.008 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-(6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	0.009 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
(rac)-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide	IC50	0.009 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-(5-((4aR,5R)-5-(Hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide and N-(5-((4aS,5S)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide	IC50	0.009 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
2-(1,1-difluoroethyl)-N-[4-methyl-3-(9-oxo-13-oxa-1,6,8-triazatricyclo[9.4.0.02,7]pentadeca-2(7),3,5-trien-4-yl)phenyl]pyridine-4-carboxamide	IC50	0.009 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
2-(1,1-difluoroethyl)-N-[3-(5-fluoro-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl]pyridine-4-carboxamide	IC50	0.009 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-[(4aS,6S)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl]-4-methylphenyl]-2-(2-fluoropropan-2-yl)pyridine-4-carboxamide	IC50	0.009 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[5-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-6-methyl-3-pyridinyl]-3-(trifluoromethyl)benzamide	IC50	0.01 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
2-(1,1-difluoroethyl)-N-[3-(6-hydroxy-6-methyl-2,4,4a,5-tetrahydro-1H-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl]pyridine-4-carboxamide	IC50	0.01 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
2-(1,1-difluoroethyl)-N-(4-methyl-3-(2,4,4a,6-tetrahydro-1H-spiro[[1,4]oxazino[4,3-a]quinoline-5,3′-oxetan]-9-yl)phenyl)isonicotinamide	IC50	0.01 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
rac-trans-N-(5-(5-(Hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide	IC50	0.01 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-[5,5-bis(hydroxymethyl)-2,4,4a,6-tetrahydro-1H-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl]-4-methylphenyl]-2-(1,1-difluoroethyl)pyridine-4-carboxamide	IC50	0.01 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
2-(1,1-difluoroethyl)-N-(4-methyl-3-(2,4,4a,6-tetrahydro-1H-spiro[[1,4]oxazino[4,3-a]quinoline-5,3′-oxetan]-9-yl)phenyl)isonicotinamide	IC50	0.011 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-[(10S)-8-ethyl-9-oxo-12-oxa-1,6,8-triazatricyclo[8.4.0.02,7]tetradeca-2(7),3,5-trien-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	0.011 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-(5-((4aR,5R)-5-(Hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide and N-(5-((4aS,5S)-5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-6-methylpyridin-3-yl)-3-(trifluoromethyl)benzamide	IC50	0.011 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-[(10S)-8-ethyl-9-oxo-12-oxa-1,5,6,8-tetrazatricyclo[8.4.0.02,7]tetradeca-2,4,6-trien-4-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	0.011 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
2-(1,1-difluoroethyl)-N-(4-methyl-3-spiro[2,4,4a,6-tetrahydro-1H-[1,4]oxazino[4,3-a][1,5]naphthyridine-5,3’-oxetane]-9-ylphenyl)pyridine-4-carboxamide	IC50	0.011 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-(5,5-difluoro-6-hydroxy-2,4,4a,6-tetrahydro-1H-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	0.011 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[5-[(4aS,6S)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl]-6-methyl-3-pyridinyl]-3-(trifluoromethyl)benzamide	IC50	0.012 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-[(4aS,6S)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl]-4-methylphenyl]-5-(trifluoromethyl)pyridine-3-carboxamide	IC50	0.012 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
9-[5-[[2-(1,1-difluoroethyl)pyridine-4-carbonyl]amino]-2-methylphenyl]-N-methyl-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridine-5-carboxamide	IC50	0.012 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
2-(1,1-difluoroethyl)-N-(3-(6-methoxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)isonicotinamide	IC50	0.013 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-[5,5-bis(hydroxymethyl)-2,4,4a,6-tetrahydro-1H-[1,4]oxazino[4,3-a]quinolin-9-yl]-4-methylphenyl]-2-(1,1-difluoroethyl)pyridine-4-carboxamide	IC50	0.013 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
(rac)-N-(4-methyl-3-(2,4,4a,6-tetrahydro-1H-spiro[[1,4]oxazino[4,3-a]quinoline-5,3′-oxetan]-9-yl)phenyl)-2-(trifluoromethyl)isonicotinamide	IC50	0.013 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
2-(1,1-difluoroethyl)-N-(3-(5-(hydroxymethyl)-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a]quinolin-9-yl)-4-methylphenyl)isonicotinamide	IC50	0.013 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-(3-((4aR,6R)-6-Hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide and N-(3-((4aS,6S)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide	IC50	0.013 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
N-[3-[(4aR,6R)-6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl]-4-methylphenyl]-2-(1,1-difluoroethyl)pyridine-4-carboxamide	IC50	0.013 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors
2-(2-cyanopropan-2-yl)-N-[3-(6-hydroxy-1,2,4,4a,5,6-hexahydro-[1,4]oxazino[4,3-a][1,5]naphthyridin-9-yl)-4-methylphenyl]pyridine-4-carboxamide	IC50	0.013 nM	US-10377770: Tricyclic compounds and compositions as kinase inhibitors

ChEMBL bioactivities

4860 potent at pChembl≥5 of 4968 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.62	IC50	0.024	nM	CHEMBL3924812
10.52	IC50	0.03	nM	CHEMBL3961999
10.41	IC50	0.039	nM	CHEMBL3933272
10.40	IC50	0.04	nM	CHEMBL3933272
10.40	IC50	0.04	nM	CHEMBL6023111
10.25	IC50	0.056	nM	CHEMBL3951474
10.22	Ki	0.06	nM	CHEMBL4776565
10.22	Ki	0.06	nM	CHEMBL5094514
10.22	IC50	0.06	nM	CHEMBL3951474
10.21	Ki	0.061	nM	CHEMBL4780060
10.21	Ki	0.061	nM	LY-3009120
10.21	Ki	0.062	nM	CHEMBL4778419
10.19	IC50	0.065	nM	CHEMBL3905257
10.15	IC50	0.07	nM	CHEMBL3905257
10.15	IC50	0.07	nM	CHEMBL5945139
10.10	IC50	0.08	nM	CHEMBL5885861
10.10	IC50	0.08	nM	CHEMBL5912922
10.10	IC50	0.08	nM	CHEMBL5937628
10.09	Ki	0.081	nM	CHEMBL4740241
10.05	IC50	0.09	nM	CHEMBL3959581
10.05	IC50	0.09	nM	CHEMBL3982146
10.05	IC50	0.09	nM	CHEMBL5808970
10.05	IC50	0.09	nM	CHEMBL5917557
10.00	IC50	0.1	nM	CHEMBL3952506
10.00	IC50	0.1	nM	CHEMBL3929689
10.00	IC50	0.1	nM	CHEMBL3956654
10.00	IC50	0.1	nM	CHEMBL3984282
10.00	IC50	0.1	nM	CHEMBL3976881
10.00	IC50	0.1	nM	CHEMBL3972141
10.00	IC50	0.1	nM	CHEMBL3928030
10.00	IC50	0.1	nM	CHEMBL3959581
10.00	IC50	0.1	nM	CHEMBL3907015
10.00	IC50	0.1	nM	CHEMBL3942721
10.00	IC50	0.1	nM	CHEMBL3966766
10.00	IC50	0.1	nM	CHEMBL3914464
10.00	IC50	0.1	nM	CHEMBL5941581
10.00	IC50	0.1	nM	CHEMBL5829780
10.00	IC50	0.1	nM	CHEMBL6032960
10.00	IC50	0.1	nM	CHEMBL5801973
10.00	IC50	0.1	nM	CHEMBL5776436
10.00	IC50	0.1	nM	CHEMBL5740520
10.00	IC50	0.1	nM	CHEMBL5966098
10.00	IC50	0.1	nM	CHEMBL5768029
10.00	IC50	0.1	nM	CHEMBL6039326
10.00	IC50	0.1	nM	CHEMBL5870489
10.00	IC50	0.1	nM	CHEMBL5814168
10.00	IC50	0.1	nM	CHEMBL5949500
10.00	IC50	0.1	nM	CHEMBL6025398
10.00	IC50	0.1	nM	CHEMBL5831664
10.00	IC50	0.1	nM	CHEMBL5862003

PubChem BioAssay actives

999 with measured affinity, of 2583 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
2-[[5-[2-methyl-5-[[2-(trifluoromethyl)pyridine-4-carbonyl]amino]phenyl]-3-morpholin-4-yl-2-pyridinyl]oxy]ethyl dihydrogen phosphate	1325769: Inhibition of 1 to 324 residues truncated c-Raf (unknown origin) expressed in baculovirus infected Sf9 insect cells using full length biotinylated MEK1 ATP binding site K97R mutant as substrate preincubated for 60 mins followed by ATP addition measured after 1 hr by alpha screen assay	ic50	<0.0001	uM
[2-hydroxy-3-[[4-[2-methyl-5-[[4-(trifluoromethyl)pyridine-2-carbonyl]amino]phenyl]-6-morpholin-4-yl-2-pyridinyl]oxy]propyl]phosphonic acid	1325769: Inhibition of 1 to 324 residues truncated c-Raf (unknown origin) expressed in baculovirus infected Sf9 insect cells using full length biotinylated MEK1 ATP binding site K97R mutant as substrate preincubated for 60 mins followed by ATP addition measured after 1 hr by alpha screen assay	ic50	<0.0001	uM
2-[[4-[2-methyl-5-[[2-(trifluoromethyl)pyridine-4-carbonyl]amino]phenyl]-6-morpholin-4-yl-2-pyridinyl]oxy]ethyl dihydrogen phosphate	1325769: Inhibition of 1 to 324 residues truncated c-Raf (unknown origin) expressed in baculovirus infected Sf9 insect cells using full length biotinylated MEK1 ATP binding site K97R mutant as substrate preincubated for 60 mins followed by ATP addition measured after 1 hr by alpha screen assay	ic50	0.0001	uM
2-[[4-[5-[[2-(1,1-difluoroethyl)pyridine-4-carbonyl]amino]-2-methylphenyl]-6-[(3R)-3-methylmorpholin-4-yl]-2-pyridinyl]oxy]ethyl dihydrogen phosphate	1325769: Inhibition of 1 to 324 residues truncated c-Raf (unknown origin) expressed in baculovirus infected Sf9 insect cells using full length biotinylated MEK1 ATP binding site K97R mutant as substrate preincubated for 60 mins followed by ATP addition measured after 1 hr by alpha screen assay	ic50	0.0001	uM
3-(2-cyanopropan-2-yl)-N-[2-fluoro-4-methyl-5-(7-methyl-8-oxopyrido[2,3-d]pyridazin-3-yl)phenyl]benzamide	1709949: Inhibition of CRAF Y340D/Y341D mutant (unknown origin) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
1-(3,3-dimethylbutyl)-3-[2-fluoro-5-[(5-fluoro-3-methyl-4-oxoquinazolin-6-yl)amino]-4-methylphenyl]urea	1709949: Inhibition of CRAF Y340D/Y341D mutant (unknown origin) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
1-[5-(3-aminoisoquinolin-7-yl)-2-fluoro-4-methylphenyl]-3-(3,3-dimethylbutyl)urea	1709949: Inhibition of CRAF Y340D/Y341D mutant (unknown origin) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
N-(4,4-dimethylpentyl)-2-fluoro-4-methyl-5-(2-methyl-1-oxophthalazin-6-yl)benzamide	1709949: Inhibition of CRAF Y340D/Y341D mutant (unknown origin) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
1-(3,3-dimethylbutyl)-3-[2-fluoro-4-methyl-5-[8-methyl-2-(methylamino)-7-oxopyrido[2,3-d]pyrimidin-6-yl]phenyl]urea	1709949: Inhibition of CRAF Y340D/Y341D mutant (unknown origin) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
3-(2-cyanopropan-2-yl)-N-[2-fluoro-4-methyl-5-(2-methyl-1-oxophthalazin-6-yl)phenyl]benzamide	1709949: Inhibition of CRAF Y340D/Y341D mutant (unknown origin) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
1-(3,3-dimethylbutyl)-3-[2-fluoro-4-methyl-5-(2-methyl-1-oxophthalazin-6-yl)phenyl]urea	1709949: Inhibition of CRAF Y340D/Y341D mutant (unknown origin) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
1-(3,3-dimethylbutyl)-3-[2-fluoro-4-methyl-5-[(3-methyl-4-oxoquinazolin-6-yl)amino]phenyl]urea	1808597: Inhibition of CRAF Y340D/Y341D mutant (unknown origin) using inactive MAP2K1 as substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
1-(6-aminopyrimidin-4-yl)-3-[5-(3,3-dimethylbutylcarbamoylamino)-4-fluoro-2-methylphenyl]-1-methylurea	1808597: Inhibition of CRAF Y340D/Y341D mutant (unknown origin) using inactive MAP2K1 as substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
5-(3,3-dimethylbutylcarbamoylamino)-4-fluoro-N-(3-methoxy-1H-pyrazolo[5,4-b]pyridin-5-yl)-2-methylbenzamide	1808597: Inhibition of CRAF Y340D/Y341D mutant (unknown origin) using inactive MAP2K1 as substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
1-(3,3-dimethylbutyl)-3-[2-fluoro-4-methyl-5-[[3-[6-(methylamino)pyrimidin-4-yl]-2-pyridinyl]amino]phenyl]urea	1808597: Inhibition of CRAF Y340D/Y341D mutant (unknown origin) using inactive MAP2K1 as substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
4-amino-N-[5-(3,3-dimethylbutylcarbamoylamino)-4-fluoro-2-methylphenyl]quinazoline-8-carboxamide	1808597: Inhibition of CRAF Y340D/Y341D mutant (unknown origin) using inactive MAP2K1 as substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
1-(3,3-dimethylbutyl)-3-[2-fluoro-4-methyl-5-[7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl]phenyl]urea	1709949: Inhibition of CRAF Y340D/Y341D mutant (unknown origin) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
N-[4-methyl-3-(6-morpholin-4-ylpyrimidin-4-yl)phenyl]-3-(trifluoromethyl)benzamide	1445038: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0001	uM
N-[3-[2-(2-hydroxyethylamino)-6-morpholin-4-ylpyrimidin-4-yl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	1545529: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0002	uM
N-[4-methyl-3-(2-morpholin-4-yl-4-pyridinyl)phenyl]-3-(trifluoromethyl)benzamide	1445038: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0002	uM
N-[3-[2-(2-hydroxyethoxy)-6-morpholin-4-yl-4-pyridinyl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	1545529: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0002	uM
N-[5-[6-[(3R,4S)-3-fluorooxan-4-yl]oxy-5-morpholin-4-yl-3-pyridinyl]-6-methyl-3-pyridinyl]-3-(trifluoromethyl)benzamide	1545529: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0003	uM
1-N-(4-chlorophenyl)-6-methyl-5-N-[3-(7H-purin-6-yl)-2-pyridinyl]isoquinoline-1,5-diamine	701679: Inhibition of C-Raf	ki	0.0003	uM
N-[4-methyl-3-(4-methyl-6-morpholin-4-yl-5-oxopyrazin-2-yl)phenyl]-3-(trifluoromethyl)benzamide	1445038: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0003	uM
N-[5-[6-(4-deuteriooxan-4-yl)oxy-5-morpholin-4-yl-3-pyridinyl]-6-methyl-3-pyridinyl]-3-(trifluoromethyl)benzamide	1545529: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0004	uM
N-[5-(6-methoxy-5-morpholin-4-yl-3-pyridinyl)-6-methyl-3-pyridinyl]-3-(trifluoromethyl)benzamide	1445038: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0004	uM
N-[4-methyl-3-(1-methyl-5-morpholin-4-yl-6-oxo-3-pyridinyl)phenyl]-3-(trifluoromethyl)benzamide	1445038: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0004	uM
N-[6-methyl-5-[5-morpholin-4-yl-6-(oxan-4-yloxy)pyridazin-3-yl]-3-pyridinyl]-3-(trifluoromethyl)benzamide	1545529: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0004	uM
2-[4-[(1E)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]ethanol	701679: Inhibition of C-Raf	ki	0.0005	uM
N-(3-tert-butylphenyl)-4-methyl-3-(6-morpholin-4-ylpyrimidin-4-yl)benzamide	1445038: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0005	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-(7H-purin-6-yl)cyclopropanecarbonyl]amino]benzamide	1534572: Inhibition of human cRAF using MEK1 (K97R) as substrate by [gamma-33P]-ATP assay	ic50	0.0005	uM
3-[[4-[4-[3-[[2-(4-chlorophenyl)acetyl]amino]phenyl]-2-cyclopropyl-1H-imidazol-5-yl]pyrimidin-2-yl]amino]benzamide	332007: Inhibition of C-RAF kinase	ic50	0.0005	uM
N-[6-methyl-5-[5-morpholin-4-yl-6-(oxan-4-yloxy)-3-pyridinyl]-3-pyridinyl]-3-(trifluoromethyl)benzamide	1445038: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0005	uM
N-[5-[6-(2-hydroxyethoxy)-5-morpholin-4-yl-3-pyridinyl]-6-methyl-3-pyridinyl]-3-(trifluoromethyl)benzamide	1445038: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0005	uM
N-[3-[2-(2-hydroxyethylamino)-6-morpholin-4-yl-4-pyridinyl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	1545529: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0006	uM
N-[3-[2-(2-hydroxyethoxy)-6-[(1R,5S)-3-oxabicyclo[3.1.0]hexan-1-yl]-4-pyridinyl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	2116948: Inhibition of C-RAF (unknown origin)	ic50	0.0006	uM
N-[3-[5-[(1-ethylpiperidin-4-yl)-methylamino]-3-pyrimidin-5-ylpyrrolo[3,2-b]pyridin-1-yl]-2,4-difluorophenyl]propane-1-sulfonamide	1380334: Inhibition of CRAF (unknown origin) by Z’-LYTE assay	ic50	0.0006	uM
N-[6-methyl-5-(5-morpholin-4-yl-6-propan-2-yloxy-3-pyridinyl)-3-pyridinyl]-3-(trifluoromethyl)benzamide	1445038: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0006	uM
2-(1,1-difluoroethyl)-N-[5-[2-(2-hydroxyethylamino)-6-morpholin-4-yl-4-pyridinyl]-6-methyl-3-pyridinyl]pyridine-4-carboxamide	1545529: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0007	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[6-(methylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480960: Inhibition of CRAF (unknown origin) using human His6-tagged MEK1 K97R mutant as substrate pretreated for 20 mins followed by [33P]-ATP addition measured after 2 hrs by filter binding method	ic50	0.0007	uM
5-(difluoromethyl)-N-[4-methyl-3-(4-oxospiro[3,5-dihydro-1,5-benzoxazepine-2,4’-oxane]-8-yl)phenyl]pyridazine-3-carboxamide	1818417: Inhibition of human recombinant cRAF measured after 60 mins by TR-FRET assay	ic50	0.0008	uM
N-[3-[5-(2-hydroxyethyl)-4-oxospiro[3H-1,5-benzoxazepine-2,4’-oxane]-8-yl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	1818417: Inhibition of human recombinant cRAF measured after 60 mins by TR-FRET assay	ic50	0.0008	uM
N-[6-methyl-5-(1-methyl-5-morpholin-4-yl-6-oxo-3-pyridinyl)-3-pyridinyl]-3-(trifluoromethyl)benzamide	1445038: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0008	uM
N-[6-methyl-5-(5-morpholin-4-yl-6-oxo-1H-pyridin-3-yl)-3-pyridinyl]-3-(trifluoromethyl)benzamide	1545529: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0009	uM
1-[(1S,1aS,6bS)-5-[(7-oxo-6,8-dihydro-5H-1,8-naphthyridin-4-yl)oxy]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-yl]-3-(2-fluorophenyl)urea	2116948: Inhibition of C-RAF (unknown origin)	ic50	0.0009	uM
4-[2-(4-bromoanilino)-1-methylbenzimidazol-5-yl]oxy-N-methylpyridine-2-carboxamide	1798620: RAF Kinase Inhibition Assay from Article 10.1021/jm801050k: “Design and Synthesis of Orally Bioavailable Benzimidazoles as Raf Kinase Inhibitors.”	ic50	0.0010	uM
N-[6-methyl-5-(1-methyl-5-morpholin-4-yl-6-oxo-3-pyridinyl)-3-pyridinyl]-2-(trifluoromethyl)pyridine-4-carboxamide	1445038: Inhibition of CRAF Y340E/Y341E mutant (unknown origin) using human MEK1 K97R mutant as substrate pretreated for 30 mins followed by substrate addition measured after 40 mins by alphascreen assay	ic50	0.0010	uM
Sorafenib	1798620: RAF Kinase Inhibition Assay from Article 10.1021/jm801050k: “Design and Synthesis of Orally Bioavailable Benzimidazoles as Raf Kinase Inhibitors.”	ic50	0.0010	uM
N-methyl-4-[[2-(4-propan-2-ylanilino)-1,3-benzoxazol-5-yl]oxy]pyridine-2-carboxamide	597805: Inhibition of c-Raf assessed as phosphorylation of MEK1/2 by ELISA	ic50	0.0010	uM
4-[[2-(4-ethylanilino)-1,3-benzoxazol-5-yl]oxy]-N-methylpyridine-2-carboxamide	597805: Inhibition of c-Raf assessed as phosphorylation of MEK1/2 by ELISA	ic50	0.0010	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	increases reaction, increases phosphorylation, decreases expression, affects binding, decreases reaction	4
Estradiol	decreases expression, increases activity, increases phosphorylation	4
Cadmium Chloride	affects phosphorylation, decreases phosphorylation, increases expression, increases reaction	4
sodium arsenite	increases activity, decreases reaction, increases phosphorylation, affects cotreatment, affects expression	3
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	increases reaction, decreases reaction, increases localization, increases phosphorylation	3
Vorinostat	decreases expression, affects cotreatment	3
Quercetin	decreases phosphorylation, decreases reaction, increases phosphorylation, decreases expression	3
geldanamycin	decreases phosphorylation, decreases expression	2
7-hydroxystaurosporine	affects cotreatment, decreases expression	2
tanespimycin	decreases expression	2
Bortezomib	affects cotreatment, decreases expression	2
Sorafenib	decreases activity	2
Wortmannin	increases reaction, increases phosphorylation	2
Arsenic Trioxide	affects cotreatment, decreases expression, increases reaction, increases expression, increases response to substance (+1 more)	2
Acetaminophen	decreases expression, increases phosphorylation, decreases reaction	2
Air Pollutants	decreases reaction, increases abundance, increases phosphorylation, increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases activity, increases phosphorylation, increases reaction, affects methylation	2
Copper	affects binding, increases expression	2
Lovastatin	increases phosphorylation, decreases activity, decreases reaction	2
Nicotine	decreases reaction, increases reaction, affects reaction, increases activity, affects binding	2
1-Methyl-4-phenylpyridinium	increases cleavage, affects expression, affects reaction	2
Paclitaxel	increases phosphorylation, affects cotreatment, decreases reaction	2
Particulate Matter	decreases reaction, increases abundance, increases phosphorylation, increases expression, affects cotreatment	2
GSK-J4	increases expression	1
ON123300	increases reaction, increases phosphorylation	1
FR900359	increases phosphorylation	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, affects expression	1
tubocapsenolide A	decreases reaction, increases degradation	1
BI-2852	decreases activity, affects binding, decreases reaction	1
quinomethionate	affects expression	1

ChEMBL screening assays

839 unique, capped per target: 803 binding, 31 functional, 5 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1001223	Binding	Inhibition of c-Raf	The identification of pyrazolo[1,5-a]pyridines as potent p38 kinase inhibitors. — *Bioorg Med Chem Lett*
CHEMBL1613772	Functional	PUBCHEM_BIOASSAY: Assay for Inhibitors of the ERK Signaling Pathway using a Homogeneous Screening Assay: c-Raf Inhibition. (Class of assay: confirmatory) [Related pubchem assays: 1454, 995 ]	PubChem BioAssay data set
CHEMBL4012741	ADMET	Activation of CRAF in human Calu6 cells assessed as increase in MEK phosphorylation at 3 uM after 2 hrs by FRET assay	Design and Discovery of N-(2-Methyl-5’-morpholino-6’-((tetrahydro-2H-pyran-4-yl)oxy)-[3,3’-bipyridin]-5-yl)-3-(trifluoromethyl)benzamide (RAF709): A Potent, Selective, and Efficacious RAF Inhibitor Targeting RAS Mutant Cancers. — *J Med Chem*

Cellosaurus cell lines

42 cell lines: 26 cancer cell line, 12 transformed cell line, 2 induced pluripotent stem cell, 1 finite cell line, 1 telomerase immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1163	D-538MG	Cancer cell line
CVCL_1266	HCC2998	Cancer cell line	Sex unspecified
CVCL_1435	MZ-MEL-2	Cancer cell line	Sex unspecified
CVCL_1636	Panc 04.03	Cancer cell line	Male
CVCL_A5QK	WMUi022-A	Induced pluripotent stem cell	Male
CVCL_B2D9	Abcam HeLa RAF1 KO	Cancer cell line	Female
CVCL_B8NM	Abcam HCT 116 RAF1 KO	Cancer cell line	Male
CVCL_B9AZ	Abcam MCF-7 RAF1 KO	Cancer cell line	Female
CVCL_B9QY	Abcam A-549 RAF1 KO	Cancer cell line	Male
CVCL_C4N9	NT-38	Cancer cell line	Female

Clinical trials (associated diseases)

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

showing 60 of 323 trials:

NCT	Phase	Status	Title
NCT03048084	Phase 4	RECRUITING	Seizure Treatment in Glioma
NCT06625047	Phase 4	COMPLETED	Comparing Telehealth and In-person Assessments in Glioma Patients Receiving Oral Chemotherapy
NCT07486713	Phase 4	RECRUITING	Olutasidenib DDI Study in Patients With IDH1 Mutation Positive Malignancies
NCT00452725	Phase 3	COMPLETED	Effect of MAXOMAT ® on the Growth of Small Children to NOONAN’s Syndrome
NCT01529840	Phase 3	COMPLETED	Somatropin Effect on Linear Growth and Final Height in Subjects With Noonan Syndrome
NCT01529944	Phase 3	COMPLETED	Genetic Testing of Noonan Subjects Previously Treated With Norditropin®. An Extension to Trial GHNOO-1658
NCT01927861	Phase 3	COMPLETED	Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome
NCT02713945	Phase 3	COMPLETED	Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
NCT05723835	Phase 3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT00045968	Phase 3	UNKNOWN	Study of a Drug [DCVax®-L] to Treat Newly Diagnosed GBM Brain Cancer
NCT00256425	Phase 3	UNKNOWN	Cognitive Rehabilitation of Glioma Patients
NCT01479686	Phase 3	COMPLETED	iMRI Guided Resection in Cerebral Glioma Surgery
NCT01502280	Phase 3	COMPLETED	Fluorescence-guided Surgery for Low- and High-grade Gliomas
NCT01655927	Phase 3	UNKNOWN	Efficacy of Tranexamic Acid in Brain Tumor Resections
NCT02363075	Phase 3	UNKNOWN	Dexamfetamine Sulphate in Patients With Glioma Suffering From Severe Asthenia
NCT03149575	Phase 3	TERMINATED	VAL-083 Phase 3 Study in Temozolomide-Avastin (Bevacizumab) Recurrent GBM
NCT03722355	Phase 3	COMPLETED	Hyperfractionated RT With BCNU Versus Conventional RT With BCNU for Supratentorial Malignant Glioma
NCT04164901	Phase 3	ACTIVE_NOT_RECRUITING	Study of Vorasidenib (AG-881) in Participants With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation (INDIGO)
NCT05303519	Phase 3	RECRUITING	SIGMA (Safusidenib in IDH1 Mutant Glioma Maintenance)
NCT05512403	Phase 3	RECRUITING	Evaluation of Diagnostic Performances of 18F-FDOPA PET KInetics
NCT05580562	Phase 3	RECRUITING	ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy (the ACTION Study)
NCT06330337	Phase 3	RECRUITING	Effect of Electroacupuncture Combined With Paclitaxel Clinical Efficacy of Patients With Recurrence of High-grade Glioma
NCT06496971	Phase 3	RECRUITING	A Prospective Pivotal Study to Evaluate the Efficacy and Safety of Avastin® Bevacizumab (BEV) With or Without Microbubble-mediated Focused Ultrasound (FUS-MB) Using NaviFUS System in Recurrent Glioblastoma Multiforme Patients
NCT06750458	Phase 3	NOT_YET_RECRUITING	Dapagliflozin Versus Dexamethasone Role in Pre-operative Management of Non- Diabetic Brain Tumor Patients
NCT07698457	Phase 3	NOT_YET_RECRUITING	Clinical Benefit of 18F-FET in Glioma.
NCT00351221	Phase 2	TERMINATED	Research Study Using Recombinant Human Insulin-Like Growth Factor-1/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 for Children With Noonan Syndrome
NCT06555237	Phase 2	RECRUITING	MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies
NCT06668805	Phase 2	RECRUITING	A Study of Vosoritide in Children With Noonan Syndrome With Inadequate Growth During or After Human Growth Hormone Treatment
NCT00047879	Phase 2	COMPLETED	Phase II Trial of Peginterferon Alpha-2b and Thalidomide in Adults With Recurrent Gliomas
NCT00107003	Phase 2	COMPLETED	GW572016 to Treat Recurrent Malignant Brain Tumors
NCT00108069	Phase 2	COMPLETED	Tamoxifen and Bortezomib to Treat Recurrent Brain Tumors
NCT00147160	Phase 2	COMPLETED	Phase II Cisplatin + Temozolomide in Malignant Glial Tumours in Children and Adolescents
NCT00165360	Phase 2	COMPLETED	Prolonged Daily Temozolomide for Low-Grade Glioma
NCT00200161	Phase 2	COMPLETED	Temozolomide & RT Followed by Dose Dense vs Temozolomide & Retinoic Acid in Pts w/Glioblastoma
NCT00213278	Phase 2	COMPLETED	Phase 2 Study of Vinblastine in Children With Recurrent or Refractory Low Grade Glioma
NCT00350727	Phase 2	COMPLETED	Pazopanib In Combination With Lapatinib In Adult Patients With Relapsed Malignant Glioma
NCT00360828	Phase 2	TERMINATED	Phase II Study of Irinotecan HCI for Recurrent Anaplastic Astrocytomas, Mixed Malignant Gliomas, and Oligodendrogliomas
NCT00389090	Phase 2	TERMINATED	A Phase II Study of Temozolomide and O6-Benzylguanine (O6-BG) in Patients With Temozolomide-Resistant Anaplastic Glioma
NCT00392171	Phase 2	COMPLETED	The Effects of Continuous 28-day (28/28) Temozolomide Chemotherapy in Subjects With Recurrent Malignant Glioma Who Have Failed the Conventional 5-day (5/28) Treatment (P04601)
NCT00404495	Phase 2	COMPLETED	Combination of Irinotecan and Temozolomide in Children With Brain Tumors.
NCT00409214	Phase 2	COMPLETED	Phase IIa Safety and Light Dose-escalation Study in Patients With Primary or Recurrent/High-grade Glioma Using the Litx™ System to Confirm the Zone of Tumor Destruction During the Intraoperative Treatment of Glioma
NCT00412542	Phase 2	COMPLETED	Thalidomide and Temozolomide or Camptothecin-11 (CPT-11) in Patients With Gliomas
NCT00424554	Phase 2	COMPLETED	Low-dose Temozolomide for 2 Weeks on Brain Tumor Enzyme in Patients With Gliomas (P04602 AM1) (Completed)
NCT00463203	Phase 2	COMPLETED	Bevacizumab and Irinotecan for Patients With Primary Brain Tumors and Progression After Standard Therapy
NCT00575796	Phase 2	UNKNOWN	Weekly Vinblastine for Chemotherapy Naive Children With Progressive Low Grade Glioma (PLGGs)
NCT00589706	Phase 2	COMPLETED	A Phase II Study of Adjuvant Use of Anti-Epidermal Growth Factor Receptor EGFR-425 in High Grade Gliomas
NCT00660283	Phase 2	UNKNOWN	A Phase II Study of Gliadel, Concomitant Temozolomide and Radiation, Followed By Dose Dense Therapy With Temozolomide For Newly Diagnosed Malignant High Grade Glioma
NCT00660621	Phase 2	UNKNOWN	A Phase II Study Of Gliadel, Concomitant Temozolomide And Radiation, Followed By Dose Dense Therapy With Temozolomide Plus Bevacizumab For Newly Diagnosed Malignant High Grade Glioma
NCT00727506	Phase 2	COMPLETED	BIBW 2992 (Afatinib) With or Without Daily Temozolomide in the Treatment of Patients With Recurrent Malignant Glioma
NCT00782626	Phase 2	COMPLETED	Everolimus (RAD001) for Children With Chemotherapy-Refractory Progressive or Recurrent Low-Grade Gliomas
NCT00795665	Phase 2	COMPLETED	Bevacizumab and Carmustine in Treating Patients With Relapsed or Progressive High-Grade Glioma
NCT01116661	Phase 2	TERMINATED	Safety Study of Aminolevulinic Acid (ALA) to Enhance Visualization and Resection of Tumors of the Brain
NCT01137604	Phase 2	COMPLETED	A Study in Subjects With Recurrent Malignant Glioma
NCT01140568	Phase 2	COMPLETED	Study of Platelet Derived Growth Factor Receptor (PDGFR) in Recurrent Malignant Gliomas
NCT01158651	Phase 2	COMPLETED	Everolimus for Children With NF1 Chemotherapy-Refractory Radiographic Progressive Low Grade Gliomas
NCT01204684	Phase 2	COMPLETED	Dendritic Cell Vaccine for Patients With Brain Tumors
NCT01229644	Phase 2	TERMINATED	Study of Crenolanib, a Selective and Potent Inhibitor of PDGFR, for the Treatment of Adult Gliomas
NCT01351519	Phase 2	TERMINATED	A Study of Aminolevulinic Acid Used to Enhance Visualization and Surgical Removal of Brain Tumors
NCT01403311	Phase 2	UNKNOWN	A Study of Aminolevulinic Acid (ALA) to Enhance Visualization and Resection of Malignant Glial Tumors of the Brain
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Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for RAF1 across ~30M SureChEMBL compounds — explore on Sugi Predict.