BRAF

Summary

BRAF (B-Raf proto-oncogene, serine/threonine kinase, HGNC:1097) is a protein-coding gene on chromosome 7q34, encoding Serine/threonine-protein kinase B-raf (P15056). Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. In precision oncology, BRAF V600E confers sensitivity to Dabrafenib/Trametinib Regimen in Anaplastic Thyroid Carcinoma (CIViC Level A); 246 further curated variant–drug associations are listed below.

This gene encodes a protein belonging to the RAF family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERK signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene, most commonly the V600E mutation, are the most frequently identified cancer-causing mutations in melanoma, and have been identified in various other cancers as well, including non-Hodgkin lymphoma, colorectal cancer, thyroid carcinoma, non-small cell lung carcinoma, hairy cell leukemia and adenocarcinoma of lung. Mutations in this gene are also associated with cardiofaciocutaneous, Noonan, and Costello syndromes, which exhibit overlapping phenotypes. A pseudogene of this gene has been identified on the X chromosome.

Source: NCBI Gene 673 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cardiofaciocutaneous syndrome (Definitive, ClinGen) — +8 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 1,561 total — 60 pathogenic, 39 likely-pathogenic
• Phenotypes (HPO): 391
• Druggable target: yes — 48 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 247 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 28 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004333

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1097
Approved symbol	BRAF
Name	B-Raf proto-oncogene, serine/threonine kinase
Location	7q34
Locus type	gene with protein product
Status	Approved
Aliases	BRAF1, BRAF-1
Ensembl gene	ENSG00000157764
Ensembl biotype	protein_coding
OMIM	164757
Entrez	673

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 11 protein_coding, 7 retained_intron, 6 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000288602, ENST00000469930, ENST00000479537, ENST00000496384, ENST00000497784, ENST00000642228, ENST00000642272, ENST00000642808, ENST00000642875, ENST00000643356, ENST00000643790, ENST00000644120, ENST00000644650, ENST00000644905, ENST00000644969, ENST00000645443, ENST00000646334, ENST00000646427, ENST00000646730, ENST00000646891, ENST00000647434, ENST00000867090, ENST00000867091, ENST00000867092, ENST00000912600, ENST00000912601, ENST00000944245

RefSeq mRNA: 13 — MANE Select: NM_004333 NM_001354609, NM_001374244, NM_001374258, NM_001378467, NM_001378468, NM_001378469, NM_001378470, NM_001378471, NM_001378472, NM_001378473, NM_001378474, NM_001378475, NM_004333

CCDS: CCDS5863, CCDS87555, CCDS94218, CCDS94219

Canonical transcript exons

ENST00000646891 — 18 exons

Exon	Start	End
ENSE00001034889	140808892	140808995
ENSE00001035295	140834609	140834872
ENSE00001862791	140924566	140924929
ENSE00003485507	140753275	140753393
ENSE00003487759	140800362	140800481
ENSE00003521664	140777991	140778075
ENSE00003527888	140776912	140777088
ENSE00003551608	140739812	140739946
ENSE00003559218	140781576	140781693
ENSE00003569635	140794308	140794467
ENSE00003587655	140749287	140749418
ENSE00003603715	140850111	140850212
ENSE00003603742	140807960	140808062
ENSE00003649805	140754187	140754233
ENSE00003680515	140787548	140787584
ENSE00003685923	140783021	140783157
ENSE00003687908	140801412	140801560
ENSE00003830897	140730665	140734770

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 97.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.6292 / max 447.2213, expressed in 1821 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86575	14.7829	1790
86574	11.3439	1774
86570	0.4032	185
86572	0.3780	75
86576	0.2151	67
86569	0.2094	67
86573	0.1575	51
86571	0.1392	53

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.92	gold quality
colonic epithelium	UBERON:0000397	92.55	gold quality
calcaneal tendon	UBERON:0003701	91.78	gold quality
middle temporal gyrus	UBERON:0002771	90.64	gold quality
sperm	CL:0000019	90.53	gold quality
sural nerve	UBERON:0015488	90.26	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.82	gold quality
adrenal tissue	UBERON:0018303	88.84	gold quality
tendon	UBERON:0000043	88.76	gold quality
male germ cell	CL:0000015	87.85	gold quality
lateral nuclear group of thalamus	UBERON:0002736	86.90	gold quality
cortical plate	UBERON:0005343	86.80	gold quality
lower esophagus mucosa	UBERON:0035834	86.17	gold quality
postcentral gyrus	UBERON:0002581	86.09	gold quality
left testis	UBERON:0004533	86.02	gold quality
testis	UBERON:0000473	85.96	gold quality
right testis	UBERON:0004534	85.87	gold quality
Brodmann (1909) area 23	UBERON:0013554	85.86	gold quality
tendon of biceps brachii	UBERON:0008188	85.56	gold quality
superior frontal gyrus	UBERON:0002661	85.12	gold quality
ganglionic eminence	UBERON:0004023	85.07	gold quality
corpus callosum	UBERON:0002336	84.91	gold quality
parietal lobe	UBERON:0001872	84.79	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.37	gold quality
bone marrow	UBERON:0002371	84.16	gold quality
upper leg skin	UBERON:0004262	84.08	gold quality
ventricular zone	UBERON:0003053	83.63	gold quality
islet of Langerhans	UBERON:0000006	83.40	gold quality
primary visual cortex	UBERON:0002436	83.24	gold quality
cerebellar cortex	UBERON:0002129	83.23	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	6838.43
E-ANND-3	yes	12.93
E-CURD-135	no	921.67
E-CURD-112	no	2.11

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
NFE2L2	Activation
SLC5A5	Repression

Upstream regulators (CollecTRI, top): CREM, LHX8, LITAF, MITF, POU3F2

miRNA regulators (miRDB)

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

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-5009-3P	99.45	69.43	1341
HSA-MIR-6507-5P	99.36	70.46	2524

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers (PMID:12068308)
• BRAF mutations in colorectal cancers occur only in tumours that do not carry mutations in a RAS gene known as KRAS, and BRAF mutation is linked to the proficiency of these tumours in repairing mismatched bases in DNA (PMID:12198537)
• High frequency of BRAF mutations in nevi (PMID:12447372)
• The V599E BRAF mutation appears to be a somatic mutation associated with melanoma development and/or progression in a proportion of affected individuals. (PMID:12619120)
• results demonstrate that the mutational status of BRAF and KRAS is distinctly different among histologic types of ovarian serous carcinoma, occurring most frequently in invasive micropapillary serous carcinomas and its precursors, serous borderline tumors (PMID:12644542)
• High prevalence of BRAF mutations in thyroid cancer is genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. (PMID:12670889)
• activating BRAF mutations may be an important event in the development of papillary thyroid cancer (PMID:12697856)
• cAMP activates ERK and increases proliferation of autosomal dominant polycystic kindey epithelial cells through the sequential phosphorylation of PKA, B-Raf and MAPK in a pathway separate from the classical receptor tyrosine kinase cascade (PMID:12753285)
• gene is mutated in skin melanoma, but not in uveal melanomas (PMID:12778069)
• 13 germline BRAF variants, 4 of which were silent mutations in coding regions & 9 nucleotide substitutions in introns, were found in melanoma patients and melanoma family, but none appeared statistically likely to be a melanoma susceptibility gene. (PMID:12810628)
• B-raf is involved in adhesion-independent ERK1/2 signaling in melanocytes (PMID:12821662)
• Data suggest that BRAF T1796A activating mutation is not common in primary uveal melanoma. (PMID:12824225)
• B-Raf has a role in extracellular signal-regulated kinase (ERK) signaling in T cells and prevents antigen-presenting cell-induced anergy (PMID:12855697)
• BRAF has a role in in squamous cell carcinoma of the head and neck through uncommon mutations (PMID:12879021)
• The BRAF(V599E) mutation appears to be an alternative event to RET/PTC rearrangement rather than to RAS mutations, which are rare in PTC. BRAF(V599E) may represent an alternative pathway to oncogenic MAPK activation in PTCs without RET/PTC activation. (PMID:12881714)
• Mucinous ovarian cancers without a KRAS mutation have not sustained alternative activation of this signaling pathway through mutation of the BRAF oncogene. (PMID:12893203)
• 3 cell lines derived from human choroidal melanoma express B-Raf containing the V599E mutation and showed a 10-fold increase in endogenous B-RafV599E kinase activity and a constitutive activation of the MEK/ERK pathway that is independent of Ras (PMID:12917419)
• Mutations are not detectable in plasma cell leukemia and multiple myeloma. (PMID:12931219)
• mutation of BRAF gene could be a potentially useful marker of prognosis of patients with advanced thyroid cancers (PMID:12970315)
• Our findings of a high frequency of BRAF mutations at codon 599 in benign melanocytic lesions of the skin indicate that this mutation is not sufficient by itself for malignant transformation. (PMID:14501284)
• Both BRAF and FBXW7 mutations functionally activate kinase effectors important in pancreatic cancer and extend potential options for therapeutic targeting of kinases in treatment of phenotypically distinct pancreatic adenocarcinoma subsets. (PMID:14507635)
• BRAF mutations, which are present in a variety of other human cancers, do not seem to be involved in gastric cancer development (PMID:14513361)
• Uceal melanomas arise independent of oncogenic BRAF and NRAS mutations. (PMID:14522897)
• BRAF mutations were seen in stomach neoplasms. (PMID:14534542)
• BRAF mutations are restricted to papillary carcinomas and poorly differentiated and anaplastic carcinomas arising from papillary carcinomas (PMID:14602780)
• BRAF is occasionally mutated in NHL, and BRAF mutation may contribute to tumor development in some NHLs (PMID:14612909)
• None of the cases of gastric cancer showed braf mutations (PMID:14618633)
• Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas (PMID:14639609)
• Missense mutation is marker of colonic but not gastric cancer. (PMID:14668801)
• Mutations were found in exon 15 in colorectal adenocarcinoma. (PMID:14688025)
• Our data indicate that BRAF gene mutations are rare to absent events in uveal melanoma of humans. (PMID:14691295)
• NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression (PMID:14695152)
• BRAF mutations are associated with proximal colon tumors with mismatch repair deficiency and MLH1 hypermethylation. (PMID:14695993)
• New enriched PCR-RFLP assay for detecting mutations of BRAF codon 599 mutation in pleural mesotheliomas. (PMID:14719068)
• RAS or BRAF mutations are detected in about 32% of all Barrett’s adenocarcinomas; the disruption of the Raf/MEK/ERK (MAPK) kinase pathway is a frequent but also early event in the development of Barrett’s adenocarcinoma (PMID:14724583)
• BRAF mutations are frequently present in sporadic colorectal cancer with methylated hMLH1 (PMID:14734469)
• Mutations in BRAF gene is associated with malignant melanomas (PMID:14961576)
• These studies identify isoprenylcysteine carboxyl methyltransferase as a potential target for reducing the growth of K-Ras- and B-Raf-induced malignancies. (PMID:14966563)
• The lack or low prevalence of BRAF mutation in other thyroid neoplasms is consistent with the notion that other previously defined genetic alterations on the same signaling pathway are sufficient to cause tumorigenesis in most thyroid neoplasms. (PMID:15001635)
• possible cooperation between BRAF activation and PTEN loss in melanoma development. (PMID:15009714)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	braf	ENSDARG00000017661
mus_musculus	Braf	ENSMUSG00000002413
rattus_norvegicus	Braf	ENSRNOG00000010957

Paralogs (23): MAP3K9 (ENSG00000006432), TESK2 (ENSG00000070759), MAP3K13 (ENSG00000073803), ARAF (ENSG00000078061), MAP3K20 (ENSG00000091436), RIPK2 (ENSG00000104312), LIMK1 (ENSG00000106683), TESK1 (ENSG00000107140), TNNI3K (ENSG00000116783), RIPK3 (ENSG00000129465), MAP3K10 (ENSG00000130758), RAF1 (ENSG00000132155), RIPK1 (ENSG00000137275), MAP3K12 (ENSG00000139625), KSR1 (ENSG00000141068), MAP3K21 (ENSG00000143674), ILK (ENSG00000166333), MLKL (ENSG00000168404), KSR2 (ENSG00000171435), MOS (ENSG00000172680), MAP3K11 (ENSG00000173327), LIMK2 (ENSG00000182541), LRRK2 (ENSG00000188906)

Protein

Protein identifiers

Serine/threonine-protein kinase B-raf — P15056 (reviewed: P15056)

Alternative names: Proto-oncogene B-Raf, p94, v-Raf murine sarcoma viral oncogene homolog B1

All UniProt accessions (11): A0A2R8Y467, A0A2R8Y492, A0A2R8Y679, A0A2R8Y8E0, A0A2R8YDP5, A0A2R8YES9, A0A2U3TZI2, P15056, H7C4S5, H7C560, H7C5K3

UniProt curated annotations — full annotation on UniProt →

Function. Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus. Phosphorylates MAP2K1, and thereby activates the MAP kinase signal transduction pathway. Phosphorylates PFKFB2. May play a role in the postsynaptic responses of hippocampal neurons.

Subunit / interactions. Monomer. Homodimer. Heterodimerizes with RAF1, and the 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 by phosphorylating BRAF at Thr-753. Heterodimerizes (via N-terminus) with KSR1 (via N-terminus) or KSR2 (via N-terminus) in a MAP2K1-dependent manner. Interacts with MAP2K1 and MAP2K2. Found in a complex with at least BRAF, HRAS, MAP2K1, MAPK3 and RGS14. Interacts with RIT1. Interacts (via N-terminus) with RGS14 (via RBD domains); the interaction mediates the formation of a ternary complex with RAF1, a ternary complex inhibited by GNAI1. Interacts with DGKH. Interacts with PRMT5. Interacts with KSR2. Interacts with AKAP13, MAP2K1 and KSR1. Identified in a complex with AKAP13, MAP2K1 and KSR1. Interacts with FNIP1 and FNIP2.

Subcellular location. Nucleus. Cytoplasm. Cell membrane.

Tissue specificity. Brain and testis.

Post-translational modifications. Phosphorylation at Ser-365 by SGK1 inhibits its activity (Ref.8, PubMed:11410590). Phosphorylation at Thr-753 by MAPK1. Dephosphorylation of Ser-365 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. Methylation at Arg-671 decreases stability and kinase activity. Ubiquitinated by RNF149; which leads to proteasomal degradation. Polyubiquitinated at Lys-578 in response to EGF.

Disease relevance. Defects in BRAF are found in a wide range of cancers. Colorectal cancer (CRC) [MIM:114500] A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. The disease may be caused by variants affecting the gene represented in this entry. Lung cancer (LNCR) [MIM:211980] A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. The gene represented in this entry is involved in disease pathogenesis. Familial non-Hodgkin lymphoma (NHL) [MIM:605027] Cancer that starts in cells of the lymph system, which is part of the body’s immune system. NHLs can occur at any age and are often marked by enlarged lymph nodes, fever and weight loss. The gene represented in this entry is involved in disease pathogenesis. Cardiofaciocutaneous syndrome 1 (CFC1) [MIM:115150] A multiple congenital anomaly disorder characterized by a distinctive facial appearance, heart defects and intellectual disability. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The disease is caused by variants affecting the gene represented in this entry. Noonan syndrome 7 (NS7) [MIM:613706] 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 3 (LPRD3) [MIM:613707] 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. A chromosomal aberration involving BRAF is found in pilocytic astrocytomas. A tandem duplication of 2 Mb at 7q34 leads to the expression of a KIAA1549-BRAF fusion protein with a constitutive kinase activity and inducing cell transformation.

Activity regulation. In quiescent cells, maintained in an inactive state via an intramolecular interaction between the protein kinase and N-terminal domains. Following mitogen-mediated cell activation, binds via its RGB domain to active HRAS (GTP-bound) which releases the inhibitory intramolecular interaction between the two domains. This allows the MAP2K1-mediated dimerization of KSR1 or KSR2, and BRAF which activates BRAF.

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

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

RefSeq proteins (13): NP_001341538, NP_001361173, NP_001361187, NP_001365396, NP_001365397, NP_001365398, NP_001365399, NP_001365400, NP_001365401, NP_001365402, NP_001365403, NP_001365404, NP_004324* (*=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)
• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

14 substrates with measured Km, best-characterized 14. 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
ATP	0.0007–0.64	11
POLY(GLU4-TYR)	0.018–0.659	10
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
EEEEYIQ[DP]-8-HYDROXY-5-(N,N-DIMETHYLSULFONAMIDO	0.057	1
S1 PEPTIDE	0.037	1
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1
EEEEY	—	0

Catalyzed reactions (Rhea), 2 shown:

• 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 (138 total): sequence variant 47, helix 20, strand 18, modified residue 14, binding site 10, mutagenesis site 7, turn 6, compositionally biased region 4, domain 2, site 2, region of interest 2, initiator methionine 1, chain 1, active site 1, cross-link 1, zinc finger region 1, sequence conflict 1

Structure

Experimental structures (PDB)

131 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8VSO	X-RAY DIFFRACTION	1.5
8JNB	X-RAY DIFFRACTION	1.62
8C7X	X-RAY DIFFRACTION	1.65
8C7Y	X-RAY DIFFRACTION	1.65
9EW6	X-RAY DIFFRACTION	1.65
8JNA	X-RAY DIFFRACTION	1.7
9BP8	X-RAY DIFFRACTION	1.73
5VYK	X-RAY DIFFRACTION	1.75
9BFB	X-RAY DIFFRACTION	1.92
7K0V	X-RAY DIFFRACTION	1.93
5ITA	X-RAY DIFFRACTION	1.95
3NY5	X-RAY DIFFRACTION	1.99
4XV9	X-RAY DIFFRACTION	2
6XFP	X-RAY DIFFRACTION	2
6N0Q	X-RAY DIFFRACTION	2.04
9AXX	X-RAY DIFFRACTION	2.07
5VAM	X-RAY DIFFRACTION	2.1
5VR3	X-RAY DIFFRACTION	2.1
6P3D	X-RAY DIFFRACTION	2.11
5JSM	X-RAY DIFFRACTION	2.19
5VAL	X-RAY DIFFRACTION	2.26
5JRQ	X-RAY DIFFRACTION	2.29
4CQE	X-RAY DIFFRACTION	2.3
9F35	X-RAY DIFFRACTION	2.3
6N0P	X-RAY DIFFRACTION	2.37
7P3V	X-RAY DIFFRACTION	2.37
3OG7	X-RAY DIFFRACTION	2.45
4XV1	X-RAY DIFFRACTION	2.47
7M0X	X-RAY DIFFRACTION	2.47
6XLO	X-RAY DIFFRACTION	2.49

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15056-F1	67.87	0.31

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 (3): 576 (proton acceptor); 380–381 (breakpoint for translocation to form kiaa1549-braf fusion protein); 438–439 (breakpoint for translocation to form kiaa1549-braf fusion protein)

Ligand- & substrate-binding residues (10): 235; 248; 251; 261; 264; 269; 272; 280; 463–471; 483

Post-translational modifications (15): 2, 151, 333, 365, 373, 396, 399, 401, 446, 447, 671, 729, 750, 753, 578

Mutagenesis-validated functional residues (7):

Position	Phenotype
53	reduces interaction with ksr1 and map2k1 and thus phosphorylation of map2k1.
88	reduces interaction with ksr1 and map2k1 and thus phosphorylation of map2k1.
483	reduces kinase activity with map2k1.
509	loss of map2k1-mediated-braf-ksr1 dimerization.
578	blocks egf-induced ubiquitination and erk activation.
666	no effect on map2k1-mediated-braf-ksr1 dimerization, however loss of braf-mediated phosphorylation of map2k1.
671	increased kinase activity and stability in response to egf treatment.

Function

Pathways and Gene Ontology

Reactome pathways

39 pathways

ID	Pathway
R-HSA-1295596	Spry regulation of FGF signaling
R-HSA-170968	Frs2-mediated activation
R-HSA-170984	ARMS-mediated activation
R-HSA-187706	Signalling to p38 via RIT and RIN
R-HSA-5673000	RAF activation
R-HSA-5674135	MAP2K and MAPK activation
R-HSA-5674499	Negative feedback regulation of MAPK pathway
R-HSA-5675221	Negative regulation of MAPK pathway
R-HSA-6802946	Signaling by moderate kinase activity BRAF mutants
R-HSA-6802948	Signaling by high-kinase activity BRAF mutants
R-HSA-6802952	Signaling by BRAF and RAF1 fusions
R-HSA-6802955	Paradoxical activation of RAF signaling by kinase inactive BRAF
R-HSA-9649948	Signaling downstream of RAS mutants
R-HSA-9656223	Signaling by RAF1 mutants
R-HSA-9726840	SHOC2 M1731 mutant abolishes MRAS complex function
R-HSA-9726842	Gain-of-function MRAS complexes activate RAF signaling
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-166520	Signaling by NTRKs
R-HSA-169893	Prolonged ERK activation events
R-HSA-187037	Signaling by NTRK1 (TRKA)
R-HSA-187687	Signalling to ERKs
R-HSA-190236	Signaling by FGFR
R-HSA-5654726	Negative regulation of FGFR1 signaling
R-HSA-5654727	Negative regulation of FGFR2 signaling
R-HSA-5654732	Negative regulation of FGFR3 signaling
R-HSA-5654733	Negative regulation of FGFR4 signaling
R-HSA-5654736	Signaling by FGFR1
R-HSA-5654738	Signaling by FGFR2
R-HSA-5654741	Signaling by FGFR3

MSigDB gene sets: 0 (showing top):

GO Biological Process (45): MAPK cascade (GO:0000165), myeloid progenitor cell differentiation (GO:0002318), protein phosphorylation (GO:0006468), epidermal growth factor receptor signaling pathway (GO:0007173), visual learning (GO:0008542), animal organ morphogenesis (GO:0009887), positive regulation of gene expression (GO:0010628), negative regulation of fibroblast migration (GO:0010764), positive regulation of D-glucose transmembrane transport (GO:0010828), synaptic vesicle exocytosis (GO:0016079), thyroid gland development (GO:0030878), T cell differentiation in thymus (GO:0033077), positive regulation of peptidyl-serine phosphorylation (GO:0033138), substrate adhesion-dependent cell spreading (GO:0034446), somatic stem cell population maintenance (GO:0035019), regulation of cell population proliferation (GO:0042127), negative regulation of apoptotic process (GO:0043066), stress fiber assembly (GO:0043149), CD4-positive, alpha-beta T cell differentiation (GO:0043367), CD4-positive or CD8-positive, alpha-beta T cell lineage commitment (GO:0043369), negative regulation of neuron apoptotic process (GO:0043524), regulation of T cell differentiation (GO:0045580), thymus development (GO:0048538), positive regulation of axon regeneration (GO:0048680), positive regulation of axonogenesis (GO:0050772), T cell receptor signaling pathway (GO:0050852), positive regulation of stress fiber assembly (GO:0051496), long-term synaptic potentiation (GO:0060291), head morphogenesis (GO:0060323), face development (GO:0060324), ERK1 and ERK2 cascade (GO:0070371), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to calcium ion (GO:0071277), cellular response to xenobiotic stimulus (GO:0071466), endothelial cell apoptotic process (GO:0072577), establishment of protein localization to membrane (GO:0090150), postsynaptic modulation of chemical synaptic transmission (GO:0099170), positive regulation of substrate adhesion-dependent cell spreading (GO:1900026), negative regulation of synaptic vesicle exocytosis (GO:2000301), negative regulation of endothelial cell apoptotic process (GO:2000352)

GO Molecular Function (17): protein kinase activity (GO:0004672), protein serine/threonine kinase activity (GO:0004674), MAP kinase kinase activity (GO:0004708), MAP kinase kinase kinase activity (GO:0004709), calcium ion binding (GO:0005509), ATP binding (GO:0005524), zinc ion binding (GO:0008270), identical protein binding (GO:0042802), scaffold protein binding (GO:0097110), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein tyrosine kinase activity (GO:0004713), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (17): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886), cilium (GO:0005929), centriolar satellite (GO:0034451), ciliary basal body (GO:0036064), neuron projection (GO:0043005), cell body (GO:0044297), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm end piece (GO:0097229), presynapse (GO:0098793), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Oncogenic MAPK signaling	5
RAF/MAP kinase cascade	3
Prolonged ERK activation events	2
Signalling to ERKs	2
Signaling by MRAS-complex mutants	2
Negative regulation of FGFR1 signaling	1
Negative regulation of FGFR2 signaling	1
Negative regulation of FGFR3 signaling	1
Negative regulation of FGFR4 signaling	1
Negative regulation of MAPK pathway	1
Signaling by RAS mutants	1
Signaling by Receptor Tyrosine Kinases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	10
protein kinase activity	3
sperm flagellum	3
synapse	3
MAPK cascade	2
protein binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
plasma membrane bounded cell projection	2
intracellular signaling cassette	1
hematopoietic progenitor cell differentiation	1
phosphorylation	1
protein modification process	1
ERBB signaling pathway	1
visual behavior	1
associative learning	1
anatomical structure morphogenesis	1
animal organ development	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
fibroblast migration	1
regulation of fibroblast migration	1
negative regulation of cell migration	1
regulation of D-glucose transmembrane transport	1
positive regulation of transmembrane transport	1
D-glucose transmembrane transport	1
neurotransmitter secretion	1
regulated exocytosis	1
establishment of localization in cell	1
presynapse	1
vesicle-mediated transport in synapse	1
synaptic vesicle cycle	1
signal release from synapse	1
endocrine system development	1
gland development	1
T cell differentiation	1
positive regulation of protein phosphorylation	1
peptidyl-serine phosphorylation	1
regulation of peptidyl-serine phosphorylation	1

Protein interactions and networks

STRING

6138 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BRAF	MAP2K1	Q02750	983
BRAF	RAF1	P04049	983
BRAF	KRAS	P01116	974
BRAF	NRAS	P01111	973
BRAF	HRAS	P01112	953
BRAF	HSP90AA1	P07900	933
BRAF	PIK3CA	P42336	931
BRAF	HSP90AB1	P08238	931
BRAF	PTEN	P60484	928
BRAF	IQGAP1	P46940	919
BRAF	KIAA1549	Q9HCM3	908
BRAF	NF1	P21359	895
BRAF	CDKN2A	P42771	886
BRAF	TP53	P04637	883
BRAF	SOS1	Q07889	881

IntAct

846 interactions, top by confidence:

A	B	Type	Score
MAP2K1	BRAF	psi-mi:“MI:0915”(physical association)	0.980
MAP2K1	BRAF	psi-mi:“MI:0407”(direct interaction)	0.980
BRAF	MAP2K1	psi-mi:“MI:0217”(phosphorylation reaction)	0.980
MAP2K1	BRAF	psi-mi:“MI:0914”(association)	0.980
BRAF	MAP2K1	psi-mi:“MI:0915”(physical association)	0.980
HRAS	RAF1	psi-mi:“MI:0914”(association)	0.980
RAF1	BRAF	psi-mi:“MI:0407”(direct interaction)	0.970
BRAF	RAF1	psi-mi:“MI:0915”(physical association)	0.970
RAF1	BRAF	psi-mi:“MI:0915”(physical association)	0.970

BioGRID (410): BRAF (Affinity Capture-MS), BRAF (Affinity Capture-MS), BRAF (Synthetic Growth Defect), BRAF (Affinity Capture-MS), BRAF (Affinity Capture-MS), BRAF (Affinity Capture-MS), BRAF (Co-localization), BRAF (Co-localization), BRAF (Co-localization), FBXW7 (Affinity Capture-Western), MAPK1 (Synthetic Lethality), FGFR2 (Negative Genetic), BRCA2 (Negative Genetic), VHL (Negative Genetic), FNTA (Negative Genetic)

ESM2 similar proteins: A0JNJ1, A5PMU4, A6QQV9, A7E3S4, D4AB98, F7EL49, P15056, P34908, P59672, P97306, Q04982, Q13905, Q15678, Q16825, Q5F488, Q5TCQ9, Q5TCZ1, Q62130, Q62136, Q62728, Q6DD51, Q6H8Q1, Q6KC51, Q6P9K8, Q6ZMT1, Q80T23, Q80YS6, Q812E4, Q8BL65, Q8BN59, Q8BZ71, Q8BZI0, Q8N556, Q8R1B0, Q8TDW5, Q8TED9, Q8TEW8, Q8VH46, Q8VHK2, Q8WXD9

Diamond homologs: A0A509AIU5, A7E3S4, D3ZG83, O01700, O19004, O55222, P00532, P04049, P04627, P05625, P06782, P09560, P10398, P10533, P11345, P14056, P15056, P18160, P18161, P27636, P27966, P28028, P34908, P57044, P80192, P83104, Q00372, Q02779, Q04982, Q13418, Q1ZXD6, Q3SWY2, Q3U1V8, Q54H45, Q54H46, Q54JC7, Q54R58, Q54TA1, Q54TM7, Q54XY6

SIGNOR signaling

70 interactions.

A	Effect	B	Mechanism
MAPK3	down-regulates	BRAF	phosphorylation
HRAS	“up-regulates activity”	BRAF	binding
KRAS	“up-regulates activity”	BRAF	binding
HRAS	up-regulates	BRAF	binding
ERK1/2	down-regulates	BRAF	phosphorylation
sorafenib	down-regulates	BRAF	“chemical inhibition”
NRAS	“up-regulates activity”	BRAF	binding
CCT239065	down-regulates	BRAF	“chemical inhibition”
GDC-0879	down-regulates	BRAF	“chemical inhibition”
AKT	down-regulates	BRAF	phosphorylation
BRAF	up-regulates	MEK1/2	phosphorylation
AKT1	“down-regulates activity”	BRAF	phosphorylation
BRAF	“up-regulates quantity”	TGFB1	relocalization
BRAF	“up-regulates activity”	MEK1/2	phosphorylation
BRAF	“down-regulates quantity by repression”	SLC5A5	“transcriptional regulation”
regorafenib	“down-regulates activity”	BRAF	“chemical inhibition”
vemurafenib	“down-regulates activity”	BRAF	“chemical inhibition”
BRAF	up-regulates	Glycolysis
ERK1/2	“down-regulates activity”	BRAF	phosphorylation
MAPK1	“down-regulates activity”	BRAF	phosphorylation
MAPK3	“down-regulates activity”	BRAF	phosphorylation
BRAF	“up-regulates activity”	ERK1/2
BRAF	“up-regulates quantity by expression”	NFE2L2	“transcriptional regulation”
Gbeta	down-regulates	BRAF	phosphorylation
RNF149	“down-regulates quantity by destabilization”	BRAF	polyubiquitination
KSR2	“up-regulates activity”	BRAF	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 97 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	7	66.6×	3e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	58.8×	7e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	58.8×	7e-10
Signaling by high-kinase activity BRAF mutants	12	47.6×	4e-15
Rap1 signalling	5	44.6×	2e-06
Activation of BH3-only proteins	7	43.5×	6e-09
MAP2K and MAPK activation	12	42.8×	8e-15
Signaling by RAF1 mutants	12	41.8×	8e-15

GO biological processes:

GO term	Partners	Fold	FDR
extrinsic apoptotic signaling pathway in absence of ligand	5	25.2×	3e-04
MAPK cascade	12	19.8×	9e-10
protein targeting	5	19.7×	7e-04
cellular senescence	5	15.9×	1e-03
Ras protein signal transduction	7	15.5×	1e-04
intracellular protein localization	10	11.2×	1e-05
negative regulation of cell population proliferation	12	5.4×	3e-04
negative regulation of apoptotic process	13	4.9×	4e-04

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

BRAF mutations are found to be recurrent in many cancer types. Of these, the mutation of valine 600 to glutamic acid (V600E) is the most prevalent. V600E has been determined to be an activating mutation, and cells that harbor it, along with other V600 mutations are sensitive to the BRAF inhibitor dabrafenib. It is also common to use MEK inhibition as a substitute for BRAF inhibitors, and the MEK inhibitor trametinib has seen some success in BRAF mutant melanomas. BRAF mutations have also been correlated with poor prognosis in many cancer types, although there is at least one study that questions this conclusion in papillary thyroid cancer. Oncogenic BRAF mutations are divided into three categories that determine their sensitivity to inhibitors. Class 1 BRAF mutations (V600) are RAS-independent, signal as monomers and are sensitive to current RAF monomer inhibitors. Class 2 BRAF mutations (K601E, K601N, K601T, L597Q, L597V, G469A, G469V, G469R, G464V, G464E, and fusions) are RAS-independent, signaling as constitutive dimers and are resistant to vemurafenib. Such mutants may be sensitive to novel RAF dimer inhibitors or MEK inhibitors. Class 3 BRAF mutations (D287H, V459L, G466V, G466E, G466A, S467L, G469E, N581S, N581I, D594N, D594G, D594A, D594H, F595L, G596D, and G596R) with low or absent kinase activity are RAS-dependent and they activate ERK by increasing their binding to activated RAS and wild-type CRAF. Class 3 BRAF mutations coexist with mutations in RAS or NF1 in melanoma may be treated with MEK inhibitors. In epithelial tumors such as CRC or NSCLC may be effectively treated with combinations that include inhibitors of receptor tyrosine kinase.

From intOGen — cancer-driver classification: activating (oncogene-like) across 28 cancer types — BLCA, BRCA, CHOL, CLLSLL, COAD, COADREAD, CSCC, DLBCLNOS, GBM, GIST, HGGNOS, LGGNOS…(+16 more).

Clinical variants and AI predictions

ClinVar

1561 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	60
Likely pathogenic	39
Uncertain significance	658
Likely benign	528
Benign	104

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1210729	NM_004333.6(BRAF):c.2125C>G (p.Gln709Glu)	Pathogenic
1317489	NM_004333.6(BRAF):c.1738A>G (p.Asn580Asp)	Pathogenic
1325840	NM_004333.6(BRAF):c.1454T>G (p.Leu485Trp)	Pathogenic
13962	NM_004333.6(BRAF):c.1385G>T (p.Arg462Ile)	Pathogenic
13963	NM_004333.6(BRAF):c.1388T>G (p.Ile463Ser)	Pathogenic
13964	NM_004333.6(BRAF):c.1391G>A (p.Gly464Glu)	Pathogenic
13965	NM_004333.6(BRAF):c.736G>C (p.Ala246Pro)	Pathogenic
13966	NM_004333.6(BRAF):c.1801A>G (p.Lys601Glu)	Pathogenic
13967	NM_004333.6(BRAF):c.1397G>T (p.Gly466Val)	Pathogenic
13968	NM_004333.6(BRAF):c.1790T>G (p.Leu597Arg)	Pathogenic
13969	NM_004333.6(BRAF):c.1789C>G (p.Leu597Val)	Pathogenic
13971	NM_004333.6(BRAF):c.1406G>C (p.Gly469Ala)	Pathogenic
13973	NM_004333.6(BRAF):c.770A>G (p.Gln257Arg)	Pathogenic
13974	NM_004333.6(BRAF):c.1406G>A (p.Gly469Glu)	Pathogenic
13975	NM_004333.6(BRAF):c.1455G>C (p.Leu485Phe)	Pathogenic
13979	NM_004333.6(BRAF):c.1741A>G (p.Asn581Asp)	Pathogenic
162793	NM_004333.6(BRAF):c.1794_1796dup (p.Thr599dup)	Pathogenic
162797	NM_004333.6(BRAF):c.1914T>G (p.Asp638Glu)	Pathogenic
1685577	NM_004333.6(BRAF):c.1591T>C (p.Trp531Arg)	Pathogenic
177672	NM_004333.6(BRAF):c.1785T>G (p.Phe595Leu)	Pathogenic
177844	NM_004333.6(BRAF):c.1455G>T (p.Leu485Phe)	Pathogenic
180784	NM_004333.6(BRAF):c.739T>C (p.Phe247Leu)	Pathogenic
180788	NM_004333.6(BRAF):c.1722C>A (p.His574Gln)	Pathogenic
180789	NM_004333.6(BRAF):c.1785T>A (p.Phe595Leu)	Pathogenic
223138	NM_004333.6(BRAF):c.1399T>G (p.Ser467Ala)	Pathogenic
2430770	NM_004333.6(BRAF):c.1591T>A (p.Trp531Arg)	Pathogenic
2501901	NM_004333.6(BRAF):c.1396G>C (p.Gly466Arg)	Pathogenic
265358	NM_004333.6(BRAF):c.1593G>T (p.Trp531Cys)	Pathogenic
2664272	NM_004333.6(BRAF):c.1799_1810delinsATG (p.Val600_Trp604delinsAspGly)	Pathogenic
2674585	NM_004333.6(BRAF):c.741T>A (p.Phe247Leu)	Pathogenic

SpliceAI

3893 predictions. Top by Δscore:

Variant	Effect	Δscore
7:140739807:CTT:C	donor_loss	1.0000
7:140739808:TTACT:T	donor_loss	1.0000
7:140739809:TACTT:T	donor_loss	1.0000
7:140739810:A:AC	donor_gain	1.0000
7:140739810:ACTTG:A	donor_loss	1.0000
7:140739811:C:CC	donor_gain	1.0000
7:140739811:CTTG:C	donor_gain	1.0000
7:140739811:CTTGG:C	donor_gain	1.0000
7:140739942:ATTAT:A	acceptor_gain	1.0000
7:140739943:TTAT:T	acceptor_gain	1.0000
7:140739944:TAT:T	acceptor_gain	1.0000
7:140739945:AT:A	acceptor_gain	1.0000
7:140739946:TCT:T	acceptor_loss	1.0000
7:140739947:C:CC	acceptor_gain	1.0000
7:140739947:CTGG:C	acceptor_loss	1.0000
7:140739948:T:A	acceptor_loss	1.0000
7:140749282:TTTA:T	donor_loss	1.0000
7:140749283:TTACC:T	donor_loss	1.0000
7:140749284:TACCT:T	donor_loss	1.0000
7:140749285:A:T	donor_loss	1.0000
7:140749286:CCTGG:C	donor_loss	1.0000
7:140749416:TGC:T	acceptor_gain	1.0000
7:140749417:GC:G	acceptor_gain	1.0000
7:140749418:CC:C	acceptor_gain	1.0000
7:140749419:C:CC	acceptor_gain	1.0000
7:140749420:T:A	acceptor_loss	1.0000
7:140749422:T:C	acceptor_gain	1.0000
7:140749422:T:TC	acceptor_gain	1.0000
7:140749428:C:CT	acceptor_gain	1.0000
7:140749429:A:C	acceptor_gain	1.0000

AlphaMissense

4976 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:140734706:G:T	P731H	1.000
7:140734707:G:A	P731S	1.000
7:140734722:G:T	R726S	1.000
7:140739827:T:A	R704S	1.000
7:140739827:T:G	R704S	1.000
7:140739828:C:G	R704T	1.000
7:140739851:G:C	C696W	1.000
7:140739853:A:G	C696R	1.000
7:140739927:C:G	R671P	1.000
7:140739930:C:A	G670V	1.000
7:140739930:C:T	G670E	1.000
7:140739931:C:G	G670R	1.000
7:140739931:C:T	G670R	1.000
7:140739938:A:C	F667L	1.000
7:140739938:A:T	F667L	1.000
7:140739939:A:G	F667S	1.000
7:140739940:A:G	F667L	1.000
7:140739940:A:T	F667I	1.000
7:140749291:T:A	D663V	1.000
7:140749292:C:G	D663H	1.000
7:140749315:G:C	P655R	1.000
7:140749315:G:T	P655H	1.000
7:140749336:T:A	E648V	1.000
7:140749342:A:G	L646P	1.000
7:140749351:C:T	G643E	1.000
7:140749352:C:G	G643R	1.000
7:140749352:C:T	G643R	1.000
7:140749357:G:T	A641E	1.000
7:140749366:T:A	D638V	1.000
7:140749366:T:C	D638G	1.000

dbSNP variants (sampled 300 via entrez): RS1000002951 (7:140776502 A>C), RS1000041082 (7:140802707 T>C), RS1000093190 (7:140845995 TA>T), RS1000116591 (7:140785320 A>T), RS1000121890 (7:140870956 G>A,C), RS1000127310 (7:140789801 G>C), RS1000133271 (7:140736975 A>C), RS1000134542 (7:140828026 A>G), RS1000137433 (7:140725717 A>G), RS1000140035 (7:140719673 G>A), RS1000170085 (7:140858369 T>C), RS1000170856 (7:140766622 G>A), RS1000173794 (7:140715263 C>T), RS1000186483 (7:140851204 T>C), RS1000194424 (7:140783806 G>A,T)

Disease associations

OMIM: gene MIM:164757 | disease phenotypes: MIM:114500, MIM:115150, MIM:155600, MIM:211980, MIM:613706, MIM:613707, MIM:163950, MIM:108010, MIM:254500, MIM:188470, MIM:208900, MIM:614429, MIM:265500, MIM:220200, MIM:606519, MIM:601518, MIM:218040, MIM:153100, MIM:151100, MIM:162900, MIM:193300, MIM:115197, MIM:192500

GenCC curated gene-disease

Disease	Classification	Inheritance
cardiofaciocutaneous syndrome 1	Definitive	Autosomal dominant
Noonan syndrome 7	Definitive	Autosomal dominant
LEOPARD syndrome 3	Definitive	Autosomal dominant
cardiofaciocutaneous syndrome	Definitive	Autosomal dominant
large congenital melanocytic nevus	Strong	Autosomal dominant
Noonan syndrome	Moderate	Autosomal dominant
Noonan syndrome with multiple lentigines	Supportive	Autosomal dominant
anaplastic astrocytoma	Limited	Autosomal dominant
Costello syndrome	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (4)

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

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

Mondo (53): RASopathy (MONDO:0021060), colorectal cancer (MONDO:0005575), cardiofaciocutaneous syndrome 1 (MONDO:0007265), melanoma, cutaneous malignant, susceptibility to, 1 (MONDO:0007963), lung cancer (MONDO:0008903), Noonan syndrome 7 (MONDO:0013379), LEOPARD syndrome 3 (MONDO:0013380), Noonan syndrome 1 (MONDO:0008104), gallbladder cancer (MONDO:0005411), endometrial carcinoma (MONDO:0002447), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), dilated cardiomyopathy (MONDO:0005021), lymphangioma (MONDO:0002013), colon carcinoma (MONDO:0002032), cancer (MONDO:0004992)

Orphanet (33): RASopathy (Orphanet:536391), Cardiofaciocutaneous syndrome (Orphanet:1340), Noonan syndrome with multiple lentigines (Orphanet:500), Familial melanoma (Orphanet:618), Noonan syndrome (Orphanet:648), Noonan syndrome and Noonan-related syndrome (Orphanet:98733), Dilated cardiomyopathy (Orphanet:217604), Differentiated thyroid carcinoma (Orphanet:146), Isolated rare lymphatic malformation (Orphanet:2415), Multiple myeloma (Orphanet:29073), Brain arteriovenous malformation (Orphanet:46724), Nephroblastoma (Orphanet:654), AL amyloidosis (Orphanet:85443), Non-Hodgkin lymphoma (Orphanet:547), Ataxia-telangiectasia (Orphanet:100)

HPO phenotypes

391 total (30 of 391 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000047	Hypospadias
HP:0000078	Abnormality of the genital system
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000141	Amenorrhea
HP:0000144	Decreased fertility
HP:0000155	Oral ulcer
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000176	Submucous cleft hard palate
HP:0000179	Thick lower lip vermilion
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000268	Dolichocephaly
HP:0000271	Abnormality of the face
HP:0000276	Long face
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000306	Abnormality of the chin
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000337	Broad forehead

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST001450_7	Response to Vitamin E supplementation	4.000000e-06
GCST003070_2	Cerebrospinal T-tau levels	3.000000e-07
GCST003079_5	Cerebrospinal fluid t-tau:AB1-42 ratio	7.000000e-06
GCST003124_32	Mild influenza (H1N1) infection	3.000000e-08
GCST004894_141	Type 2 diabetes	1.000000e-09
GCST004894_65	Type 2 diabetes	4.000000e-07
GCST008103_6	Bipolar disorder	6.000000e-10
GCST009600_92	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	5.000000e-09
GCST010118_157	Type 2 diabetes	2.000000e-10
GCST012210_2	Longevity	1.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004760	t-tau measurement
EFO:0007708	t-tau:beta-amyloid 1-42 ratio measurement
EFO:1001488	influenza A (H1N1)

MeSH disease descriptors (27)

Descriptor	Name	Tree numbers
D001260	Ataxia Telangiectasia	C10.228.140.252.190.530.060; C10.562.100; C10.597.350.090.500.530.060; C14.907.823.213; C16.320.080; C16.320.798.250; C18.452.284.060; C20.673.795.250
D002289	Carcinoma, Non-Small-Cell Lung	C04.588.894.797.520.109.220.249; C08.381.540.140.500; C08.785.520.100.220.500
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D015179	Colorectal Neoplasms	C04.588.274.476.411.307; C06.301.371.411.307; C06.405.249.411.307; C06.405.469.158.356; C06.405.469.491.307; C06.405.469.860.180
D056685	Costello Syndrome	C05.660.207.219; C16.131.077.256; C16.320.188
D003616	Dandy-Walker Syndrome	C10.228.140.252.300; C10.228.140.602.500; C10.500.205; C16.131.666.205
D006345	Heart Septal Defects, Ventricular	C14.240.400.560.540; C14.280.400.560.540; C16.131.240.400.560.540
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D002538	Intracranial Arteriovenous Malformations	C10.228.140.300.520; C10.500.190.500; C14.240.850.750.295; C14.240.850.875.500; C14.907.150.295; C14.907.253.560.400; C16.131.240.850.750.295; C16.131.240.850.875.500; C16.131.666.190.500
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
D008202	Lymphangioma	C04.557.375.450
D016403	Lymphoma, Large B-Cell, Diffuse	C04.557.386.480.150.585; C15.604.515.569.480.150.585; C20.683.515.761.480.150.585
D008228	Lymphoma, Non-Hodgkin	C04.557.386.480; C15.604.515.569.480; C20.683.515.761.480
D008545	Melanoma	C04.557.465.625.650.510; C04.557.580.625.650.510; C04.557.665.510; C04.588.805.377; C17.800.882.445
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
D009208	Myoepithelioma	C04.557.435.585
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690
D054079	Vascular Malformations	C14.240.850; C16.131.240.850
D009396	Wilms Tumor	C04.557.435.595; C04.588.945.947.535.585; C04.700.900; C12.050.351.937.820.535.585; C12.050.351.968.419.473.585; C12.200.758.820.750.585; C12.200.777.419.473.585; C12.900.820.535.585; C12.950.419.473.585; C12.950.983.535.585; C16.320.700.900
D006623	von Hippel-Lindau Disease	C10.562.925; C14.907.077.925; C16.131.077.245.750; C16.320.184.750
C535579	Cardiofaciocutaneous syndrome (supp.)
C566169	Cardiomyopathy, Familial Hypertrophic, 4 (supp.)
C580062	Epidermal Nevus (supp.)
C537846	Noonan like syndrome (supp.)
C572845	Thyroid cancer, follicular (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL3559685 (PROTEIN FAMILY), CHEMBL3883317 (PROTEIN FAMILY), CHEMBL4106189 (PROTEIN COMPLEX), CHEMBL4523687 (PROTEIN-PROTEIN INTERACTION), CHEMBL5145 (SINGLE PROTEIN), CHEMBL5291967 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

48 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 622,897 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1229517	VEMURAFENIB	4	15,704
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1421	DASATINIB ANHYDROUS	4	55,003
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL1834657	INFIGRATINIB PHOSPHATE	4	285
CHEMBL1852688	INFIGRATINIB	4	2,209
CHEMBL1946170	REGORAFENIB	4	12,678
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL2146883	COBIMETINIB	4	9,422
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL3301610	ABEMACICLIB	4	7,045
CHEMBL3301612	ENCORAFENIB	4	4,624
CHEMBL3348923	TOVORAFENIB	4	834
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL5416410	DASATINIB	4	655
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL939	GEFITINIB	4	117,814
CHEMBL941	IMATINIB	4	111,611
CHEMBL1908391	MASITINIB	3
CHEMBL3264002	AVUTOMETINIB	3
CHEMBL4583691	NAPORAFENIB	3
CHEMBL50	QUERCETIN	3
CHEMBL572881	MOTESANIB	3
CHEMBL103667	DORAMAPIMOD	2
CHEMBL1230609	FORETINIB	2
CHEMBL1738757	REBASTINIB	2
CHEMBL2029988	CEP-32496	2
CHEMBL206834	BAFETINIB	2

Clinical evidence (CIViC)

Drug × variant × indication: 247 predictive associations from 330 curated evidence items; also 26 prognostic, 7 functional, 5 diagnostic, 2 oncogenic.

Variant	Therapy	Indication	Effect	Level	CIViC
BRAF V600E	Dabrafenib/Trametinib Regimen	Anaplastic Thyroid Carcinoma	Sensitivity/Response	CIViC A	EID10785 +5
BRAF V600E	Dabrafenib	Melanoma	Sensitivity/Response	CIViC A	EID11244 +5
BRAF V600	Cobimetinib + Vemurafenib	Melanoma	Sensitivity/Response	CIViC A	EID6044 +1
BRAF V600E	Dabrafenib + Trametinib	Pleomorphic Xanthoastrocytoma	Sensitivity/Response	CIViC A	EID11312 +1
BRAF V600E	Vemurafenib	Skin Melanoma	Sensitivity/Response	CIViC A	EID1409 +1
BRAF V600	Vemurafenib	Erdheim-Chester Disease	Sensitivity/Response	CIViC A	EID11237
BRAF V600	Atezolizumab + Vemurafenib + Cobimetinib	Melanoma	Sensitivity/Response	CIViC A	EID11238
BRAF V600	Dabrafenib + Trametinib	Skin Melanoma	Sensitivity/Response	CIViC A	EID1411
BRAF V600	Encorafenib + Binimetinib	Melanoma	Sensitivity/Response	CIViC A	EID7287
BRAF V600 OR v::BRAF Fusion	Tovorafenib	Childhood Low-grade Glioma	Sensitivity/Response	CIViC A	EID12028
BRAF V600E	Dabrafenib + Trametinib	Pilocytic Astrocytoma	Sensitivity/Response	CIViC A	EID11313
BRAF V600E	Trametinib + Dabrafenib	Solid Tumor	Sensitivity/Response	CIViC A	EID12161
BRAF V600E	Dabrafenib + Trametinib	Low Grade Glioma	Sensitivity/Response	CIViC A	EID12162
BRAF V600E	Dabrafenib + Trametinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC A	EID3017
BRAF V600E	Cetuximab + Encorafenib	Colorectal Cancer	Sensitivity/Response	CIViC A	EID9851
BRAF V600E OR KIAA1549::BRAF Fusion	Tovorafenib	Childhood Low-grade Glioma	Sensitivity/Response	CIViC A	EID12016
BRAF V600E	Vemurafenib	Melanoma	Sensitivity/Response	CIViC B	EID1398 +14
BRAF V600K	Vemurafenib	Melanoma	Sensitivity/Response	CIViC B	EID1399 +9
BRAF V600E	Vemurafenib	Hairy Cell Leukemia	Sensitivity/Response	CIViC B	EID11315 +6
BRAF V600E	Vemurafenib	Colorectal Cancer	Sensitivity/Response	CIViC B	EID1405 +4
BRAF V600E	Vemurafenib	Papillary Thyroid Carcinoma	Sensitivity/Response	CIViC B	EID1591 +4
BRAF V600E	Vemurafenib	Lung Adenocarcinoma	Sensitivity/Response	CIViC B	EID3782 +3
BRAF V600E	Trametinib	Melanoma	Sensitivity/Response	CIViC B	EID2135 +2
BRAF V600K	Dabrafenib + Trametinib	Melanoma	Sensitivity/Response	CIViC B	EID6939 +2
BRAF V600	Vemurafenib	Langerhans-cell Histiocytosis	Sensitivity/Response	CIViC B	EID11302 +1
BRAF V600	Dabrafenib + Trametinib	Melanoma	Sensitivity/Response	CIViC B	EID6180 +1
BRAF V600E	Panitumumab + Vemurafenib	Colorectal Cancer	Sensitivity/Response	CIViC B	EID1413 +1
BRAF V600E	Vemurafenib + Irinotecan + Cetuximab	Colorectal Cancer	Sensitivity/Response	CIViC B	EID1902 +1
BRAF V600E	Selumetinib	High Grade Glioma	Sensitivity/Response	CIViC B	EID2145 +1
BRAF V600E	Vemurafenib	Anaplastic Thyroid Carcinoma	Sensitivity/Response	CIViC B	EID6045 +1

+217 more predictive associations (showing top 30 by evidence level).

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs113488022	BRAF		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — RAF family

Most potent curated ligand interactions (30 total), top 25:

Ligand	Action	Affinity	Parameter
GDC-0879	Inhibition	9.89	pIC50
SB590885	Inhibition	9.8	pKi
naporafenib	Inhibition	8.89	pKd
vemurafenib	Inhibition	8.54	pIC50
dabrafenib	Inhibition	8.49	pIC50
exarafenib	Inhibition	8.46	pIC50
tinlorafenib	Inhibition	8.24	pIC50
XP-102	Binding	8.22	pKd
brimarafenib	Inhibition	8.1	pIC50
TAK-632	Inhibition	8.08	pIC50
mosperafenib	Inhibition	8.05	pKd
LY3009120	Inhibition	8.04	pIC50
L779450	Inhibition	8.0	pIC50
LUT014	Inhibition	7.88	pIC50
plixorafenib	Inhibition	7.85	pIC50
sorafenib	Inhibition	7.66	pIC50
regorafenib	Inhibition	7.55	pIC50
CCT241161	Inhibition	7.52	pIC50
lifirafenib	Inhibition	7.49	pIC50
claturafenib	Inhibition	7.46	pEC50
agerafenib	Inhibition	7.44	pKd
NST-628	Binding	7.3	pKd
belvarafenib	Inhibition	7.25	pIC50
CCT196969	Inhibition	7.0	pIC50
PLX-4720	Inhibition	6.8	pIC50

Binding affinities (BindingDB)

3524 measured of 4193 human assays (4196 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(1Z)-5-[1-methyl-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2,3-dihydro-1H-indene-1-hydroxylamine	IC50	0.02 nM
(1Z)-5-[1-(piperidin-4-yl)-3-(pyridin-4-yl)-1H-pyrazol-4-yl]-2,3-dihydro-1H-indene-1-hydroxylamine	IC50	0.03 nM
N-[4-methyl-3-(4-morpholin-4-ylthieno[3,2-d]pyrimidin-2-yl)phenyl]-3-(trifluoromethyl)benzamide	IC50	0.039 nM	US-9242969: Biaryl amide compounds as kinase inhibitors
(1S,3R)-3-{4-[(1Z)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridin-4-yl)-1H-pyrazol-1-yl}cyclohexan-1-ol	IC50	0.04 nM
3-(difluoromethyl)-N-[4-methyl-3-(8-morpholin-4-ylimidazo[1,2-b]pyridazin-6-yl)phenyl]benzamide	IC50	0.04 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
3-{4-[(1Z)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridin-4-yl)-1H-pyrazol-1-yl}propan-1-ol	IC50	0.05 nM
3-(difluoromethyl)-N-[4-methyl-3-(2-morpholin-4-yl-4-pyridinyl)phenyl]benzamide	IC50	0.056 nM	US-9242969: Biaryl amide compounds as kinase inhibitors
N-[4-methyl-3-(8-morpholin-4-ylimidazo[1,2-a]pyrazin-6-yl)phenyl]-3-(trifluoromethyl)benzamide	IC50	0.065 nM	US-9242969: Biaryl amide compounds as kinase inhibitors
6-cyclopropyl-N-[3-[2-(2-hydroxyethoxy)-6-morpholin-4-yl-4-pyridinyl]-4-methylphenyl]pyridazine-4-carboxamide	IC50	0.07 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[(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]-4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)benzamide	IC50	0.079 nM	US-9670231: Fused tricyclic amide compounds as multiple kinase inhibitors
N-[3-[5-(2-aminopyrimidin-4-yl)-2-tert-butyl-1H-imidazol-4-yl]-5-chloro-2-fluorophenyl]propane-1-sulfonamide	IC50	0.08 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
N-[5-chloro-3-[5-[2-(2-cyanoethylamino)pyrimidin-4-yl]-2-cyclopropyl-1H-imidazol-4-yl]-2-fluorophenyl]methanesulfonamide	IC50	0.08 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
N-[3-[2-(ethylamino)-6-morpholin-4-ylpyrimidin-4-yl]-4-methylphenyl]-3-methylsulfonylbenzamide	IC50	0.08 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[3-[2-(azetidin-3-yloxy)-6-morpholin-4-ylpyrimidin-4-yl]-4-methylphenyl]-2-(2-cyanopropan-2-yl)pyridine-4-carboxamide	IC50	0.08 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[4-methyl-3-(4-morpholin-4-yl-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl]-3-(trifluoromethyl)benzamide	IC50	0.08 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[(1S,1aS,6bS)-5-[(2-oxo-3,4-dihydro-1H-pyrido[2,3-d]pyrimidin-5-yl)oxy]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-1-yl]-4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)benzamide	IC50	0.085 nM	US-9670231: Fused tricyclic amide compounds as multiple kinase inhibitors
(1R,3R)-3-{4-[(1Z)-1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl]-3-(pyridin-4-yl)-1H-pyrazol-1-yl}cyclohexan-1-ol	IC50	0.09 nM
N-[4-chloro-3-(1-methyl-5-morpholin-4-yl-6-oxo-3-pyridinyl)phenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	IC50	0.09 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
2-cyclopropyl-N-[3-[2-(2-hydroxyethoxy)-6-morpholin-4-yl-4-pyridinyl]-4-methylphenyl]pyridine-4-carboxamide	IC50	0.09 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
methyl N-[(2S)-1-[[4-[2-tert-butyl-4-[3-chloro-5-(propylsulfonylamino)phenyl]-1H-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate	IC50	0.1 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
methyl N-[(2S)-1-[[4-[2-tert-butyl-4-[3-chloro-5-(cyclopropylsulfonylamino)phenyl]-1H-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate	IC50	0.1 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
methyl N-[(2S)-1-[[4-[2-tert-butyl-4-[3-chloro-5-(ethylsulfonylamino)phenyl]-1H-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate	IC50	0.1 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
N-[3-[5-(2-aminopyrimidin-4-yl)-2-cyclopropyl-1H-imidazol-4-yl]-5-chloro-2-fluorophenyl]-2,6-difluorobenzenesulfonamide	IC50	0.1 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
methyl N-[(2S)-1-[[4-[4-[2-chloro-3-[(2,6-difluorophenyl)sulfonylamino]-5-fluorophenyl]-2-cyclopropyl-1H-imidazol-5-yl]pyrimidin-2-yl]amino]propan-2-yl]carbamate	IC50	0.1 nM	US-8563553: Compounds and compositions as protein kinase inhibitors
N-[4-methyl-3-[2-morpholin-4-yl-6-(3-oxomorpholin-4-yl)pyrimidin-4-yl]phenyl]-3-(trifluoromethyl)benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
5-(dimethylamino)-N-[3-(2,6-dimorpholin-4-ylpyrimidin-4-yl)-4-methylphenyl]pyridine-3-carboxamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[4-methyl-3-(2-methylsulfonyl-6-morpholin-4-ylpyrimidin-4-yl)phenyl]-3-(trifluoromethyl)benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[3-(2-imidazol-1-yl-6-morpholin-4-ylpyrimidin-4-yl)-4-methylphenyl]-3-(trifluoromethyl)benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[4-methyl-3-(2-morpholin-4-yl-4-pyridinyl)phenyl]-3-methylsulfonylbenzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[5-(2,6-dimorpholin-4-yl-4-pyridinyl)-6-methyl-3-pyridinyl]-3-(trifluoromethyl)benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[3-[1-(cyanomethyl)-5-morpholin-4-yl-6-oxo-3-pyridinyl]-4-methylphenyl]-3-(trifluoromethyl)benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
3-(1,1-difluoroethyl)-N-[4-methyl-3-(1-methyl-5-morpholin-4-yl-6-oxo-3-pyridinyl)phenyl]benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
3-(difluoromethyl)-N-[3-(6-ethoxy-5-morpholin-4-yl-3-pyridinyl)-4-methylphenyl]benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[5-[6-(dimethylamino)-5-morpholin-4-yl-3-pyridinyl]-6-methyl-3-pyridinyl]-3-(trifluoromethyl)benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
2-(1,1-difluoropropyl)-N-[4-methyl-3-(1-methyl-2-morpholin-4-yl-6-oxo-4-pyridinyl)phenyl]pyridine-4-carboxamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
2-ethyl-N-[4-methyl-3-(1-methyl-2-morpholin-4-yl-6-oxo-4-pyridinyl)phenyl]pyridine-4-carboxamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
2-(1-cyanocyclopropyl)-N-[4-methyl-3-(1-methyl-2-morpholin-4-yl-6-oxo-4-pyridinyl)phenyl]pyridine-4-carboxamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
3-(difluoromethyl)-N-[4-methyl-3-(1-methyl-2-morpholin-4-yl-6-oxo-4-pyridinyl)phenyl]benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
2-(1,1-difluoroethyl)-N-[3-(1-ethyl-2-morpholin-4-yl-6-oxo-4-pyridinyl)-4-methylphenyl]pyridine-4-carboxamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
3-(difluoromethyl)-N-[3-(6-ethoxy-5-morpholin-4-ylpyridazin-3-yl)-4-methylphenyl]benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[4-methyl-3-[5-morpholin-4-yl-6-(oxan-4-yloxy)pyridazin-3-yl]phenyl]-4-(trifluoromethyl)pyridine-2-carboxamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
2-(1-cyanocyclopropyl)-N-[4-methyl-3-(1-methyl-5-morpholin-4-yl-6-oxopyridazin-3-yl)phenyl]pyridine-4-carboxamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
2-(1-cyanocyclopropyl)-N-[3-[2-(ethylamino)-6-morpholin-4-ylpyrimidin-4-yl]-4-methylphenyl]pyridine-4-carboxamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
5-cyclopropyl-N-[6-methyl-5-(4-morpholin-4-yl-1H-imidazo[4,5-c]pyridin-6-yl)-3-pyridinyl]-1,2-oxazole-3-carboxamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[4-methyl-3-(4-morpholin-4-yl-5H-pyrrolo[3,2-d]pyrimidin-2-yl)phenyl]-3-(trifluoromethyl)benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[4-methyl-3-(1-methyl-7-morpholin-4-ylpyrazolo[4,5-d]pyrimidin-5-yl)phenyl]-3-(trifluoromethyl)benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
3-(difluoromethyl)-N-[4-methyl-3-(8-morpholin-4-ylimidazo[1,2-a]pyridin-6-yl)phenyl]benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
3-(difluoromethyl)-N-[4-methyl-3-(4-morpholin-4-yl-5,5-dioxo-6,7-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl]benzamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
2-(1,1-difluoroethyl)-N-[6-methyl-5-(8-morpholin-4-ylimidazo[1,2-b]pyridazin-6-yl)-3-pyridinyl]pyridine-4-carboxamide	IC50	0.1 nM	US-9694016: Biaryl amide compounds as kinase inhibitors
N-[5-chloro-3-[5-[2-(2-cyanoethylamino)pyrimidin-4-yl]-2-(1-methylcyclopropyl)-1H-imidazol-4-yl]-2-fluorophenyl]methanesulfonamide	IC50	0.11 nM	US-8563553: Compounds and compositions as protein kinase inhibitors

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.70	IC50	0.02	nM	CHEMBL500659
10.70	IC50	0.02	nM	CHEMBL5885861
10.52	IC50	0.03	nM	CHEMBL526479
10.47	IC50	0.034	nM	CHEMBL5289891
10.40	IC50	0.04	nM	CHEMBL498344
10.30	IC50	0.05	nM	CHEMBL527029
10.30	IC50	0.05	nM	CHEMBL5850574
10.18	IC50	0.066	nM	CHEMBL5591799
10.15	IC50	0.07	nM	CHEMBL5087577
10.10	IC50	0.08	nM	CHEMBL3651664
10.10	IC50	0.08	nM	CHEMBL3651683
10.10	IC50	0.08	nM	CHEMBL5982580
10.05	IC50	0.09	nM	CHEMBL521562
10.00	IC50	0.1	nM	CHEMBL3752213
10.00	IC50	0.1	nM	CHEMBL3651662
10.00	IC50	0.1	nM	CHEMBL3651665
10.00	IC50	0.1	nM	CHEMBL3651609
10.00	IC50	0.1	nM	CHEMBL3651610
10.00	IC50	0.1	nM	CHEMBL3651613
10.00	IC50	0.1	nM	CHEMBL5287468
9.99	Ki	0.102	nM	CHEMBL4740241
9.96	IC50	0.11	nM	CHEMBL2047875
9.96	IC50	0.11	nM	CHEMBL3651658
9.96	IC50	0.11	nM	CHEMBL3651680
9.96	IC50	0.1096	nM	CHEMBL2047875
9.96	IC50	0.11	nM	CHEMBL1276186
9.92	IC50	0.12	nM	CHEMBL3651703
9.92	Ki	0.12	nM	CHEMBL4776565
9.89	Ki	0.13	nM	CHEMBL525191
9.89	IC50	0.13	nM	CHEMBL3651661
9.89	IC50	0.13	nM	CHEMBL3651695
9.89	IC50	0.13	nM	CHEMBL3651701
9.89	IC50	0.13	nM	CHEMBL525191
9.89	IC50	0.13	nM	CHEMBL2139930
9.89	Ki	0.13	nM	CHEMBL5566280
9.86	Ki	0.139	nM	LY-3009120
9.82	IC50	0.152	nM	CHEMBL3933272
9.82	IC50	0.15	nM	CHEMBL500406
9.82	IC50	0.15	nM	CHEMBL5795266
9.82	IC50	0.15	nM	CHEMBL5835573
9.80	Ki	0.16	nM	SB590885
9.80	IC50	0.16	nM	CHEMBL3651697
9.80	IC50	0.16	nM	SB590885
9.80	IC50	0.16	nM	CHEMBL5811533
9.80	IC50	0.16	nM	CHEMBL1276179
9.80	Kd	0.16	nM	SB590885
9.78	Ki	0.165	nM	CHEMBL5090624
9.77	Ki	0.17	nM	CHEMBL525191
9.77	IC50	0.17	nM	CHEMBL525191
9.74	IC50	0.18	nM	CHEMBL2047879

PubChem BioAssay actives

3236 with measured affinity, of 6100 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
(NE)-N-[5-(1-methyl-3-pyridin-4-ylpyrazol-4-yl)-2,3-dihydroinden-1-ylidene]hydroxylamine	362268: Inhibition of human recombinant B-Raf by fluorescence anisotropy	ic50	<0.0001	uM
(NE)-N-[5-(1-piperidin-4-yl-3-pyridin-4-ylpyrazol-4-yl)-2,3-dihydroinden-1-ylidene]hydroxylamine	1127836: Inhibition of BRAF (unknown origin)	ic50	<0.0001	uM
N-[3-[[4-[6-(3-fluorophenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl]amino]propyl]benzenesulfonamide	2116956: Inhibition of B-RAF V600E mutant (unknown origin) expressed in HEK293 cells in presence of tracer incubated for 1 hr by NanoBRET assay	ic50	<0.0001	uM
cis-(1S,3R)-3-[4-[(1E)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]cyclohexan-1-ol	362268: Inhibition of human recombinant B-Raf by fluorescence anisotropy	ic50	<0.0001	uM
2-[4-[(1E)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]ethanol	1166978: Inhibition of BRAF V600E mutant (unknown origin)	ki	0.0001	uM
(NE)-N-[5-(5-pyridin-4-yl-1H-pyrazol-4-yl)-2,3-dihydroinden-1-ylidene]hydroxylamine	362268: Inhibition of human recombinant B-Raf by fluorescence anisotropy	ic50	0.0001	uM
3-[5-[2-[2-(5-methyl-1,1-dioxo-1,2,5-thiadiazolidin-2-yl)ethylamino]pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl]phenol	1823586: Inhibition of human BRAF V600E mutant using myelin basic protein as substrate in presence of [gamma-33P]ATP incubated for 40 mins by scintillation counting method	ic50	0.0001	uM
1-(3,3-dimethylbutyl)-3-[2-fluoro-5-[(5-fluoro-3-methyl-4-oxoquinazolin-6-yl)amino]-4-methylphenyl]urea	1709948: Inhibition of BRAF (unknown origin) (416 to 766) 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	1709948: Inhibition of BRAF (unknown origin) (416 to 766) 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	1709948: Inhibition of BRAF (unknown origin) (416 to 766) 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	1709948: Inhibition of BRAF (unknown origin) (416 to 766) 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	1709948: Inhibition of BRAF (unknown origin) (416 to 766) 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	1709948: Inhibition of BRAF (unknown origin) (416 to 766) 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	1808598: Inhibition of BRAF (unknown origin) (416 to 766) 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	1808598: Inhibition of BRAF (unknown origin) (416 to 766) 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	1808598: Inhibition of BRAF (unknown origin) (416 to 766) 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	1808598: Inhibition of BRAF (unknown origin) (416 to 766) inactive MAP2K1 as substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0001	uM
2-[4-[(2Z)-2-hydroxyimino-1,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]ethanol	2110290: Inhibition of BRAF V600E mutant (unknown origin) assessed as inhibition constant	ki	0.0001	uM
2-[4-[(1Z)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]ethanol	1928017: Inhibition of B-Raf in human A-375 cells	ic50	0.0001	uM
trans-(1R,3R)-3-[4-[(1E)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]cyclohexan-1-ol	362268: Inhibition of human recombinant B-Raf by fluorescence anisotropy	ic50	0.0001	uM
3-[4-[(1E)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]propan-1-ol	362268: Inhibition of human recombinant B-Raf by fluorescence anisotropy	ic50	0.0001	uM
7-[2-chloro-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]-3-(1H-indazol-4-yl)-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidine	537782: Inhibition of BRAF	ic50	0.0001	uM
3-(7-fluoro-1H-indazol-4-yl)-7-[2-fluoro-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidine	537782: Inhibition of BRAF	ic50	0.0001	uM
7-[2,6-difluoro-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]-3-(7-fluoro-1H-indazol-4-yl)-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidine	537782: Inhibition of BRAF	ic50	0.0001	uM
(NE)-N-[5-[1-(oxan-4-yl)-3-pyridin-4-ylpyrazol-4-yl]-2,3-dihydroinden-1-ylidene]hydroxylamine	1127836: Inhibition of BRAF (unknown origin)	ic50	0.0002	uM
N-[2,4-difluoro-3-[[3-(7H-purin-6-yl)-2-pyridinyl]amino]phenyl]-1H-pyrazole-4-sulfonamide	1298015: Inhibition of B-Raf V600E mutant (unknown origin) assessed as MEK1 phosphorylation using MEK1-Avitag as substrate after 1 hr by HTRF assay	ic50	0.0002	uM
(NE)-N-[5-[(2-pyrimidin-2-ylfuro[2,3-c]pyridin-3-yl)amino]-2,3-dihydroinden-1-ylidene]hydroxylamine	568446: Inhibition of B-Raf V600E mutant	ic50	0.0002	uM
(NE)-N-[5-[2-[4-[2-(dimethylamino)ethoxy]phenyl]-5-pyridin-4-yl-1H-imidazol-4-yl]-2,3-dihydroinden-1-ylidene]hydroxylamine	1380302: Inhibition of full length human 6His-tagged BRAF V600E mutant expressed in baculovirus infected insect cells co-expressing human CDC37 (1 to 378 residues) using MEK1 as substrate after 30 mins	ic50	0.0002	uM
N-(3-chlorophenyl)-4-methyl-3-[[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclopropanecarbonyl]amino]benzamide	1534573: Inhibition of human GST-tagged BRAF V600E mutant (416 to 766 residues) using human full length 6His-tagged MEK1 (K97R) as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by filter binding method	ic50	0.0002	uM
3-(2-cyanopropan-2-yl)-N-[2-fluoro-4-methyl-5-(7-methyl-8-oxopyrido[2,3-d]pyridazin-3-yl)phenyl]benzamide	1709948: Inhibition of BRAF (unknown origin) (416 to 766) assessed as using inactive phosphorylated MAP2K1 substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0002	uM
5-(3,3-dimethylbutylcarbamoylamino)-4-fluoro-N-(3-methoxy-1H-pyrazolo[5,4-b]pyridin-5-yl)-2-methylbenzamide	1808598: Inhibition of BRAF (unknown origin) (416 to 766) inactive MAP2K1 as substrate preincubated for 30 mins measured after 90 mins by DELFIA assay	ki	0.0002	uM
7-[2,6-difluoro-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]-3-(1H-indazol-4-yl)-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidine	537782: Inhibition of BRAF	ic50	0.0002	uM
(NE)-N-[5-[1-[3-(methylamino)cyclohexyl]-3-pyridin-4-ylpyrazol-4-yl]-2,3-dihydroinden-1-ylidene]hydroxylamine	362268: Inhibition of human recombinant B-Raf by fluorescence anisotropy	ic50	0.0002	uM
7-[2-fluoro-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]-3-(1H-indazol-4-yl)-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidine	537782: Inhibition of BRAF	ic50	0.0002	uM
3-[(5-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4-(dimethylamino)-N-methylbenzenesulfonamide	1245734: Inhibition of His6-tagged full length BRAF V600E mutant (2 to 766 residues) (unknown origin) expressed in Baculovirus expression system by BRAMA method	ic50	0.0002	uM
2,6-difluoro-N-(3-methoxy-1H-pyrazolo[5,4-b]pyridin-5-yl)-3-(thiophen-2-ylsulfonylamino)benzamide	616548: Inhibition of full length B-Raf V600E mutant	ic50	0.0002	uM
trans-(1S,2S)-2-[4-[(1E)-1-hydroxyimino-2,3-dihydroinden-5-yl]-3-pyridin-4-ylpyrazol-1-yl]cyclopentan-1-ol	362268: Inhibition of human recombinant B-Raf by fluorescence anisotropy	ic50	0.0003	uM
(NE)-N-[5-[1-(1-methylpiperidin-4-yl)-3-pyridin-4-ylpyrazol-4-yl]-2,3-dihydroinden-1-ylidene]hydroxylamine	1127836: Inhibition of BRAF (unknown origin)	ic50	0.0003	uM
N-(3-chlorophenyl)-4-methyl-3-[[1-[6-(methylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480956: Inhibition of recombinant human N-terminal GST-tagged BRAF catalytic domain (416 to 766 residues) V600E mutant expressed in baculovirus expression system 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	0.0003	uM
N-[3-(2-acetamidoimidazo[1,2-a]pyridin-6-yl)-4-methylphenyl]-3-tert-butylbenzamide	1367757: Inhibition of recombinant C-terminal his6-tagged B-Raf (437 to 765 residues) V600E mutant (unknown origin) catalytic domain expressed in baculovirus infected Sf21 insect cells using biotinylated Mek substrate preincubated for 60 mins measured after 3 hrs by amplified luminescence proximity homogeneous assay	ic50	0.0003	uM
N-[3-(2-acetamidoimidazo[1,2-a]pyridin-6-yl)-4-methylphenyl]-3-chlorobenzamide	1367757: Inhibition of recombinant C-terminal his6-tagged B-Raf (437 to 765 residues) V600E mutant (unknown origin) catalytic domain expressed in baculovirus infected Sf21 insect cells using biotinylated Mek substrate preincubated for 60 mins measured after 3 hrs by amplified luminescence proximity homogeneous assay	ic50	0.0003	uM
N-[2-chloro-3-[(3,5-dimethyl-4-oxoquinazolin-6-yl)amino]-4,5-difluorophenyl]propane-1-sulfonamide	2116959: Inhibition of B-RAF V600E (unknown origin)	ic50	0.0003	uM
4-amino-N-[6-chloro-3-[(2-chlorophenyl)sulfonylamino]-2-fluorophenyl]-6-(1,3-dimethylpyrazol-4-yl)quinazoline-8-carboxamide	1678651: Inhibition of of human recombinant His6-tagged B-Raf V600E mutant expressed in baculovirus infected cells co-expresing CDC37 in presence of [gamma33P]ATP incubated for 60 mins by scintillation counting method	ki	0.0003	uM
(2S,4R)-1-[(2S)-2-[5-[2-[2-[2-[[4-[3-[2,6-difluoro-3-(propylsulfonylamino)benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl]benzoyl]amino]ethoxy]ethoxy]ethoxy]pentanoylamino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1854376: Inhibition of BRAF V600E mutant (unknown origin) using MEK1 (K97R) as substrate in presence of [gamma-33P]ATP by radiometric assay	ic50	0.0003	uM
1-[3-[3-(4-chloro-3-hydroxyphenyl)-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-7-yl]-8-azabicyclo[3.2.1]octan-8-yl]ethanone	446542: Inhibition of B-Raf	ic50	0.0003	uM
2-chloro-5-[7-[4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenyl]-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-3-yl]phenol	469343: Inhibition of human recombinant B-Raf expressed in Sf9 cells assessed as inhibition of Mek1 phosphorylation	ic50	0.0003	uM
ethyl 3-[3-(3-hydroxy-4-methylphenyl)-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-7-yl]-8-azabicyclo[3.2.1]octane-8-carboxylate	446542: Inhibition of B-Raf	ic50	0.0003	uM
3-[7-[2-chloro-4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]phenyl]-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-3-yl]phenol	469343: Inhibition of human recombinant B-Raf expressed in Sf9 cells assessed as inhibition of Mek1 phosphorylation	ic50	0.0003	uM
3-[7-[4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-methylphenyl]-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-3-yl]phenol	469343: Inhibition of human recombinant B-Raf expressed in Sf9 cells assessed as inhibition of Mek1 phosphorylation	ic50	0.0003	uM
3-[7-[4-[(1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-2-fluorophenyl]-2-pyridin-4-ylpyrazolo[1,5-a]pyrimidin-3-yl]phenol	469343: Inhibition of human recombinant B-Raf expressed in Sf9 cells assessed as inhibition of Mek1 phosphorylation	ic50	0.0003	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Vemurafenib	increases expression, affects phosphorylation, decreases activity, affects response to substance, decreases reaction (+9 more)	11
dabrafenib	affects reaction, affects response to substance, affects cleavage, increases response to substance, decreases reaction (+2 more)	4
Sorafenib	decreases activity, decreases reaction, increases phosphorylation	3
Valproic Acid	decreases expression	3
sodium arsenite	affects expression, increases expression	2
tanespimycin	increases expression, decreases expression	2
5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide	decreases expression, increases expression	2
trametinib	affects expression, affects response to substance, increases phosphorylation, affects phosphorylation, affects cotreatment (+3 more)	2
Vorinostat	affects cotreatment, affects expression, affects reaction, affects response to substance, increases expression	2
Cadmium	decreases expression	2
Cannabidiol	affects cotreatment, decreases expression	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
GSK-J4	increases expression	1
2-methoxy-6-undecyl-1,4-benzoquinone	decreases expression	1
A-1155463	affects reaction, affects response to substance, decreases reaction, increases response to substance	1
FR900359	affects phosphorylation	1
triphenyl(phenylethynyl)phosphonium	decreases expression	1
moringin	affects cotreatment, decreases expression	1
APS-2-79	increases response to substance, affects reaction, increases phosphorylation	1
intybin	decreases phosphorylation	1
betulin	affects response to substance, affects reaction, decreases cleavage, affects cotreatment	1
allyl isothiocyanate	decreases phosphorylation	1
pirinixic acid	affects binding, decreases expression, increases activity	1
ascofuranone	decreases reaction, increases phosphorylation	1
bisphenol A	increases reaction, increases expression, increases phosphorylation, affects response to substance, decreases expression	1
trichostatin A	decreases expression	1
afimoxifene	affects cotreatment, increases activity, increases expression, increases phosphorylation	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
dictamnine	decreases phosphorylation	1

ChEMBL screening assays

1442 unique, capped per target: 1400 binding, 37 functional, 5 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3882094	Binding	Inhibition of N-terminal GST-tagged recombinant human C-Raf Y340D/Y341D double mutant expressed in baculovirus infected Sf21 insect cells using MEK1 as substrate preincubated for 5 mins followed by substrate addition measured after 30 mins	Multi-functional small molecules as anti-proliferative agents
CHEMBL1047416	Functional	Inhibition of Braf in human A375 cells assessed as inhibition of ERK phosphorylation	Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline. — J Med Chem
CHEMBL4024633	ADMET	Inhibition of full length His6-tagged BRAF (unknown origin) expressed in baculovirus expression system assessed as reduction in MEK phosphorylation by measuring ADP production by BRAMA	4,6-Diaminopyrimidines as Highly Preferred Troponin I-Interacting Kinase (TNNI3K) Inhibitors. — J Med Chem

Cellosaurus cell lines

1,677 cell lines: 1,660 cancer cell line, 9 induced pluripotent stem cell, 3 transformed cell line, 2 telomerase immortalized cell line, 1 undefined cell line type, 1 finite cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0015	U-266/70	Cancer cell line	Male
CVCL_0016	U-266/84	Cancer cell line	Male
CVCL_0040	WM115	Cancer cell line	Female
CVCL_0062	MDA-MB-231	Cancer cell line	Female
CVCL_0068	SK-MEL-1	Cancer cell line	Male
CVCL_0080	A-673	Cancer cell line	Female
CVCL_0124	435.eB	Cancer cell line	Male
CVCL_0132	A-375	Cancer cell line	Female
CVCL_0136	A375.S2	Cancer cell line	Female
CVCL_0144	ARO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03975829	PHASE4	RECRUITING	Pediatric Long-Term Follow-up and Rollover Study
NCT00114829	PHASE4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	PHASE4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	PHASE4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	PHASE4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00129870	PHASE4	TERMINATED	CONCEPT: Comparison of Oxaliplatin vs Conventional Methods With Calcium/Magnesium in First-Line Metastatic Colorectal Cancer
NCT00138060	PHASE4	COMPLETED	Toxicity/Benefit Ratio Optimization of Chemotherapy in Colorectal Cancer (CRC) Patients by Determination of Individual Genotypic Determinants
NCT00216424	PHASE4	TERMINATED	Capecitabine (Xeloda) and Radiation for Patients With Rectosigmoid Carcinoma
NCT00327093	PHASE4	TERMINATED	Elaboration of a Model for Predicting Efficacy of Monoclonal Antibodies (Cetuximab and Bevacizumab) in Patients With Colorectal Cancer and Liver Metastases
NCT00332943	PHASE4	COMPLETED	MR Colonography With Fecal Tagging. Barium vs. BariumFerumoxsil
NCT00441311	PHASE4	COMPLETED	Dissemination of Colorectal Cancer Screening to Primary Care Physicians
NCT00460837	PHASE4	WITHDRAWN	Comparison of Bowel Preparation in Virtual Colonoscopy (VC) - Patient Experience
NCT00473980	PHASE4	COMPLETED	Preoperative Non-steroidal Anti-inflammatory Drugs(NSAID) to Colorectal Cancer Patients
NCT00488904	PHASE4	COMPLETED	Omega-3 Fatty Acids and Postoperative Complications After Colorectal Surgery
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00502671	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) as Adjuvant Monotherapy in Patients With Colon Cancer.
NCT00559676	PHASE4	COMPLETED	Study of Biomarkers in Patients Undergoing Chemotherapy for Metastatic Colorectal Cancer
NCT00577031	PHASE4	COMPLETED	OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.
NCT00626054	PHASE4	COMPLETED	Comparison of Two Methods of Administration of a PEG Solution
NCT00812864	PHASE4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00868569	PHASE4	UNKNOWN	Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer
NCT00868816	PHASE4	COMPLETED	Oxaliplatine Based Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: 8 Cycles Versus 12 Cycles
NCT00874406	PHASE4	UNKNOWN	Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer
NCT00928928	PHASE4	COMPLETED	Oxidative Stress Markers in Open and Laparoscopic Colectomy for Cancer
NCT00942461	PHASE4	COMPLETED	Inflammatory Response in Laparoscopic and Open Colectomy
NCT01023633	PHASE4	UNKNOWN	OPTIMOX1 in Chinese mCRC Patients
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01315990	PHASE4	UNKNOWN	FOLFIRI in Combination With Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer Including a Regular Dermal Prophylaxis to Prevent Acneiforme Follicular Exanthema
NCT01493713	PHASE4	COMPLETED	Correlation Between RECIST, Morphologic Response by CT- Histopathologic Response in Hepatic Metastasis Secondary to Colorectal Cancer
NCT01609660	PHASE4	COMPLETED	Impact of Probiotics on the Intestinal Microbiota
NCT01641458	PHASE4	COMPLETED	Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
NCT01689792	PHASE4	COMPLETED	A Multi-centre Study Comparing the Polyp Detection Rate of Two Different Types of Bowel Preparation: a 2-litre Solution (MOVIPREP®) Versus a Hyperosmotic and Stimulant Combined Low Volume Bowel Preparation (Sodium Picosulfate and Magnesium Citrate)
NCT01695772	PHASE4	COMPLETED	A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer
NCT01695863	PHASE4	COMPLETED	Efficacy and Patient Satisfaction of Miralax and Gatorade Versus Movi Prep
NCT01706822	PHASE4	TERMINATED	Radial Reload Laparoscopic LAR Case Series
NCT01740947	PHASE4	TERMINATED	Does Administration of Antibiotics in Patients Undergoing Surgery for Colorectal Cancer Result in Less Complications and Better Prognosis?
NCT01831310	PHASE4	COMPLETED	Nutrition for Colorectal Cancer Patients and Neutrophil Functions
NCT01841294	PHASE4	UNKNOWN	NK Activity Modulation Induced by Intravenous Lidocaine During Colorectal Laparoscopic Surgery
NCT01959061	PHASE4	UNKNOWN	Efficacy and Safety of Raltitrexed-based Transarterial Chemoembolisation(TACE)for Colorectal Cancer Liver Metastases
NCT02032953	PHASE4	UNKNOWN	Enhancing the Anabolic Effect of Perioperative Nutrition With Insulin While Maintaining Normoglycemia