ARAF

Summary

ARAF (A-Raf proto-oncogene, serine/threonine kinase, HGNC:646) is a protein-coding gene on chromosome Xp11.3, encoding Serine/threonine-protein kinase A-Raf (P10398). Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. In precision oncology, ARAF S214C confers sensitivity to Sorafenib in Lung Non-small Cell Carcinoma (CIViC Level C); 2 further curated variant–drug associations are listed below.

Enables protein serine/threonine kinase activity. Involved in negative regulation of apoptotic process; regulation of TOR signaling; and regulation of protein metabolic process. Predicted to be active in cytosol and mitochondrion. Biomarker of high grade glioma.

Source: NCBI Gene 369 — RefSeq curated summary.

At a glance

• Gene–disease (curated): diffuse lymphatic malformation (Limited, GenCC)
• Clinical variants (ClinVar): 115 total — 3 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 2
• Druggable target: yes — 9 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 3 curated variant–drug associations
• Cancer driver (intOGen): activating (oncogene-like) across 3 cancer types
• MANE Select transcript: NM_001654

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:646
Approved symbol	ARAF
Name	A-Raf proto-oncogene, serine/threonine kinase
Location	Xp11.3
Locus type	gene with protein product
Status	Approved
Aliases	A-Raf
Ensembl gene	ENSG00000078061
Ensembl biotype	protein_coding
OMIM	311010
Entrez	369

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 29 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000377039, ENST00000377045, ENST00000469505, ENST00000470206, ENST00000489496, ENST00000895638, ENST00000895639, ENST00000895640, ENST00000895641, ENST00000895642, ENST00000895643, ENST00000895644, ENST00000895645, ENST00000895646, ENST00000895647, ENST00000895648, ENST00000895649, ENST00000895650, ENST00000895651, ENST00000895652, ENST00000895653, ENST00000895654, ENST00000895655, ENST00000895656, ENST00000914655, ENST00000914656, ENST00000914657, ENST00000914658, ENST00000914659, ENST00000951036, ENST00000951037, ENST00000951038

RefSeq mRNA: 3 — MANE Select: NM_001654 NM_001256196, NM_001256197, NM_001654

CCDS: CCDS35232, CCDS59164

Canonical transcript exons

ENST00000377045 — 16 exons

Exon	Start	End
ENSE00000669309	47564985	47565139
ENSE00000669315	47566884	47566911
ENSE00000669321	47568718	47568894
ENSE00000669340	47569893	47570024
ENSE00001043742	47566639	47566780
ENSE00001043758	47565252	47565350
ENSE00001093194	47562909	47563063
ENSE00001472613	47569539	47569657
ENSE00001740061	47568987	47569033
ENSE00001832535	47561205	47561251
ENSE00001936221	47571323	47571908
ENSE00003512527	47563226	47563329
ENSE00003548197	47564797	47564899
ENSE00003563389	47570878	47571012
ENSE00003717973	47567230	47567432
ENSE00003738733	47566986	47567131

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 96.98.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 41.0830 / max 280.5447, expressed in 1821 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196207	41.0830	1821

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	96.98	gold quality
granulocyte	CL:0000094	96.35	gold quality
gastrocnemius	UBERON:0001388	96.00	gold quality
body of stomach	UBERON:0001161	95.51	gold quality
apex of heart	UBERON:0002098	95.30	gold quality
body of pancreas	UBERON:0001150	95.28	gold quality
muscle of leg	UBERON:0001383	95.23	gold quality
right lobe of liver	UBERON:0001114	95.21	gold quality
mucosa of stomach	UBERON:0001199	94.89	gold quality
metanephros cortex	UBERON:0010533	94.72	gold quality
transverse colon	UBERON:0001157	94.71	gold quality
right lobe of thyroid gland	UBERON:0001119	94.67	gold quality
left uterine tube	UBERON:0001303	94.67	gold quality
left coronary artery	UBERON:0001626	94.64	gold quality
upper lobe of left lung	UBERON:0008952	94.64	gold quality
popliteal artery	UBERON:0002250	94.63	gold quality
tibial artery	UBERON:0007610	94.62	gold quality
mucosa of transverse colon	UBERON:0004991	94.60	gold quality
left lobe of thyroid gland	UBERON:0001120	94.57	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.57	gold quality
left adrenal gland	UBERON:0001234	94.56	gold quality
coronary artery	UBERON:0001621	94.53	gold quality
left adrenal gland cortex	UBERON:0035825	94.47	gold quality
right coronary artery	UBERON:0001625	94.46	gold quality
aorta	UBERON:0000947	94.39	gold quality
right adrenal gland	UBERON:0001233	94.38	gold quality
triceps brachii	UBERON:0001509	94.36	gold quality
right ovary	UBERON:0002118	94.25	gold quality
minor salivary gland	UBERON:0001830	94.24	gold quality
right adrenal gland cortex	UBERON:0035827	94.22	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ERF, ZHX2

miRNA regulators (miRDB)

35 targeting ARAF, 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-6856-5P	100.00	65.47	1298
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6737-3P	98.95	68.56	1577
HSA-MIR-7157-3P	98.95	68.70	1582
HSA-MIR-5008-3P	98.73	67.50	1433
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-6842-3P	98.07	66.33	1325
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-3127-5P	97.52	65.24	786
HSA-MIR-4456	97.50	64.88	1678
HSA-MIR-1289	97.46	65.37	655

Literature-anchored findings (GeneRIF, showing 23)

• In a two-hybrid screen of human fetal liver cDNA library, TH1 was detected as a new interaction partner of A-Raf; this specific interaction may have played a critical role in the activation of A-Raf. (PMID:11952167)
• A-Raf kinase is negatively regulated by trihydrophobin 1 (PMID:14684750)
• mutation analysis of the conserved regions in the ARAF gene in human colorectal adenocarcinoma (PMID:14688025)
• A-Raf residues are identified that bind to specific phosphoinositides, possibly as a mechanism to localize the enzyme to particular membrane microdomains rich in these phospholipids. (PMID:15736953)
• These data reveal that B-RAF is an important mediator of neuronal survival, migration, and dendrite formation and that A-RAF cannot fully compensate for these functions. (PMID:16980614)
• Positive regulation of A-RAF by phosphorylation of isoform-specific hinge segment and identification of novel phosphorylation sites. (PMID:18662992)
• hnRNP H blocks MST2-mediated apoptosis in cancer cells by regulating A-Raf transcription. (PMID:20145135)
• study investigated role of ARAF in cancer cell signaling and examined the role of ARAF in mediating paradoxical activation of the MAPK pathway in cells treated with RAF inhibitors; ARAF seems to stabilize BRAF:CRAF complexes in cells treated with RAF inhibitors and regulate cell signaling in a subtle manner to ensure signaling efficiency (PMID:22926515)
• Ras pathway activation via EGF treatment induced strong binding between B-Raf and C-Raf and a low level of binding between B-Raf and A-Raf. (PMID:23352452)
• show that Araf antagonizes mesendoderm induction and patterning activity of Nodal/Smad2 signals in vertebrate embryos by directly inhibiting Smad2 signalling (PMID:23591895)
• Galpha12-ARAF-ERK pathway stimulates RFFL transcription through the transcription factor c-Myc. (PMID:24114843)
• The study identifies somatic activating ARAF mutations in Langerhans cell histiocytosis. (PMID:24652991)
• Dimerization of the kinase ARAF promotes MAPK pathway activation and cell migration. (PMID:25097033)
• analysis of FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma (PMID:25608663)
• Aberrant expression of A-, B-, and C-RAF, and COT is frequent in PTC; increased expression of COT is correlated with recurrence of PTC. (PMID:25674762)
• This review discusses the regulation of A-Raf protein expression, and the roles of A-Raf in apoptosis and cancer, with a special focus on its role in resistance to Raf inhibitors. [review] (PMID:26508523)
• The constitutive or induced re-localization of A-Raf to the plasma membrane compromises its ability to efficiently sequester and inactivate MST2, thus rendering cells susceptible to apoptosis (PMID:26891695)
• Linc01232 promotes the metastasis of pancreatic cancer by suppressing the ubiquitin-mediated degradation of HNRNPA2B1 and activating the A-Raf-induced MAPK/ERK signaling pathway. (PMID:32814086)
• ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma. (PMID:33953400)
• ARAF suppresses ERBB3 expression and metastasis in a subset of lung cancers. (PMID:35302851)
• ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1. (PMID:35613620)
• Somatic ARAF mutations in pediatric Langerhans cell histiocytosis: clinicopathologic, genetic and functional profiling. (PMID:37572153)
• A-Raf interacts with MEK1 and activates MEK1 by phosphorylation. (PMID:8621729)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	araf	ENSDARG00000054533
mus_musculus	Araf	ENSMUSG00000001127
rattus_norvegicus	Araf	ENSRNOG00000010838

Paralogs (23): MAP3K9 (ENSG00000006432), TESK2 (ENSG00000070759), MAP3K13 (ENSG00000073803), MAP3K20 (ENSG00000091436), RIPK2 (ENSG00000104312), LIMK1 (ENSG00000106683), TESK1 (ENSG00000107140), TNNI3K (ENSG00000116783), RIPK3 (ENSG00000129465), MAP3K10 (ENSG00000130758), RAF1 (ENSG00000132155), RIPK1 (ENSG00000137275), MAP3K12 (ENSG00000139625), KSR1 (ENSG00000141068), MAP3K21 (ENSG00000143674), BRAF (ENSG00000157764), ILK (ENSG00000166333), MLKL (ENSG00000168404), KSR2 (ENSG00000171435), MOS (ENSG00000172680), MAP3K11 (ENSG00000173327), LIMK2 (ENSG00000182541), LRRK2 (ENSG00000188906)

Protein

Protein identifiers

Serine/threonine-protein kinase A-Raf — P10398 (reviewed: P10398)

Alternative names: Proto-oncogene A-Raf, Proto-oncogene A-Raf-1, Proto-oncogene Pks

All UniProt accessions (3): P10398, A0A024R178, Q96II5

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May also regulate the TOR signaling cascade. Phosphorylates PFKFB2. Serves as a positive regulator of myogenic differentiation by inducing cell cycle arrest, the expression of myogenin and other muscle-specific proteins, and myotube formation.

Subunit / interactions. Interacts with TH1L/NELFD.

Tissue specificity. Predominantly in urogenital tissues.

Post-translational modifications. Dephosphorylation of Ser-214 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.

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

Miscellaneous. Has a wider tissue distribution than isoform 1, and acts as a dominant-negative antagonist.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P10398-1	1	yes
P10398-2	2, DA-Raf1

RefSeq proteins (3): NP_001243125, NP_001243126, NP_001645* (*=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), 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 (47 total): binding site 10, modified residue 9, strand 8, sequence conflict 4, sequence variant 3, domain 2, splice variant 2, helix 2, region of interest 2, chain 1, zinc finger region 1, turn 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
8VSL	X-RAY DIFFRACTION	1.42
8VSM	X-RAY DIFFRACTION	1.5
8VSN	X-RAY DIFFRACTION	1.91
9AXM	X-RAY DIFFRACTION	2.42
1WXM	SOLUTION NMR
2MSE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10398-F1	70.99	0.34

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): 429 (proton acceptor)

Ligand- & substrate-binding residues (10): 115; 125; 128; 133; 136; 144; 316–324; 336; 99; 112

Post-translational modifications (9): 157, 162, 181, 186, 214, 253, 257, 269, 318

Function

Pathways and Gene Ontology

Reactome pathways

20 pathways

ID	Pathway
R-HSA-5673000	RAF activation
R-HSA-5674135	MAP2K and MAPK activation
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-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-6802949	Signaling by RAS mutants
R-HSA-6802957	Oncogenic MAPK signaling
R-HSA-9660537	Signaling by MRAS-complex mutants

MSigDB gene sets: 261 (showing top): GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_PEPTIDYL_SERINE_MODIFICATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, HSIAO_HOUSEKEEPING_GENES, KEGG_ERBB_SIGNALING_PATHWAY, GOBP_REGULATION_OF_PEPTIDYL_SERINE_PHOSPHORYLATION, GOBP_REGULATION_OF_CATABOLIC_PROCESS, KEGG_PATHWAYS_IN_CANCER, GOBP_POSITIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, KEGG_PROSTATE_CANCER, KEGG_RENAL_CELL_CARCINOMA, GOBP_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, MORF_PML, KEGG_COLORECTAL_CANCER

GO Biological Process (8): MAPK cascade (GO:0000165), regulation of TOR signaling (GO:0032006), regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032434), positive regulation of peptidyl-serine phosphorylation (GO:0033138), protein modification process (GO:0036211), negative regulation of apoptotic process (GO:0043066), protein phosphorylation (GO:0006468), signal transduction (GO:0007165)

GO Molecular Function (11): 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), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (3): cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Oncogenic MAPK signaling	7
RAF/MAP kinase cascade	3
Signaling by MRAS-complex mutants	2
Signaling by RAS mutants	1
Disease	1
MAPK1/MAPK3 signaling	1
Signal Transduction	1
MAPK family signaling cascades	1
Diseases of signal transduction by growth factor receptors and second messengers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	2
cellular anatomical structure	2
cytoplasm	2
intracellular signaling cassette	1
TOR signaling	1
regulation of intracellular signal transduction	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
regulation of proteasomal protein catabolic process	1
regulation of ubiquitin-dependent protein catabolic process	1
positive regulation of protein phosphorylation	1
peptidyl-serine phosphorylation	1
regulation of peptidyl-serine phosphorylation	1
protein metabolic process	1
macromolecule modification	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
phosphorylation	1
protein modification process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
MAPK cascade	1
protein serine/threonine kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

221 interactions, top by confidence:

A	B	Type	Score
HRAS	RAF1	psi-mi:“MI:0914”(association)	0.980
MAP2K1	RAF1	psi-mi:“MI:0914”(association)	0.960
BRAF	HRAS	psi-mi:“MI:0914”(association)	0.940
MAP2K2	ARAF	psi-mi:“MI:0915”(physical association)	0.910
ARAF	MAP2K2	psi-mi:“MI:0915”(physical association)	0.910
MAP2K2	ARAF	psi-mi:“MI:0407”(direct interaction)	0.910
ARAF	BRAF	psi-mi:“MI:2364”(proximity)	0.890
ARAF	BRAF	psi-mi:“MI:0915”(physical association)	0.890
HRAS	ARAF	psi-mi:“MI:0407”(direct interaction)	0.850
RAD51D	RAD51B	psi-mi:“MI:0914”(association)	0.850
MAP2K2	RAF1	psi-mi:“MI:0914”(association)	0.850
ARAF	HRAS	psi-mi:“MI:0915”(physical association)	0.850
YWHAQ	WDR62	psi-mi:“MI:0914”(association)	0.830
YWHAE	ARAF	psi-mi:“MI:0915”(physical association)	0.810
TIRAP	TLR4	psi-mi:“MI:0914”(association)	0.810
HSP90AB1	ARAF	psi-mi:“MI:0915”(physical association)	0.810
ARAF	HSP90AB1	psi-mi:“MI:0915”(physical association)	0.810
YWHAH	ABLIM1	psi-mi:“MI:0914”(association)	0.800
SFN	ARAF	psi-mi:“MI:0915”(physical association)	0.760
YWHAH	FAM83G	psi-mi:“MI:0914”(association)	0.710

BioGRID (538): KRAS (Two-hybrid), AGTRAP (Two-hybrid), ARAF (Affinity Capture-MS), ACTA2 (Affinity Capture-MS), AIFM1 (Affinity Capture-MS), ATP5B (Affinity Capture-MS), BAG2 (Affinity Capture-MS), CALU (Affinity Capture-MS), YBX3 (Affinity Capture-MS), CTNNA1 (Affinity Capture-MS), DDX5 (Affinity Capture-MS), DNAJA1 (Affinity Capture-MS), DNAJA2 (Affinity Capture-MS), DPM1 (Affinity Capture-MS), EEF2 (Affinity Capture-MS)

ESM2 similar proteins: A2VDU3, A7E3S4, O19004, O35346, O42565, O43318, O54785, P00531, P04049, P04627, P05625, P09560, P0C8E4, P10398, P11345, P11346, P14056, P15056, P27966, P28028, P34152, P34908, P53666, P53668, P53669, P53670, P53671, P97306, Q00944, Q04982, Q05397, Q32L23, Q3UVC0, Q5R5M7, Q5RFL3, Q61083, Q61084, Q61097, Q62073, Q6VAB6

Diamond homologs: A0A509AH51, A0QNG1, A3B529, A3LUB9, A5D791, A6ZU08, A7E3S4, A8X0C4, A8XSC1, D0Z5N4, D4A7V9, E2QWQ2, O19004, P00531, P00532, P04049, P04627, P05625, P07527, P0CS76, P0CS77, P10398, P11345, P14056, P17157, P19525, P27636, P32490, P33279, P34331, P38990, P41676, P43637, P50750, P52304, P53351, P54666, Q03957, Q03963, Q04770

SIGNOR signaling

15 interactions.

A	Effect	B	Mechanism
2-chloro-5-(2-phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)phenol	down-regulates	ARAF	“chemical inhibition”
ARAF	up-regulates	MAP2K2	phosphorylation
HRAS	up-regulates	ARAF	binding
NRAS	up-regulates	ARAF	binding
ARAF	up-regulates	MAP2K1	phosphorylation
PAK1	up-regulates	ARAF	phosphorylation
ARAF	up-regulates	MEK1/2	phosphorylation
ARAF	“up-regulates activity”	SLC9A3R2	phosphorylation
KSR2	“up-regulates activity”	ARAF	binding
KSR1	“up-regulates activity”	ARAF	binding
ARAF	“down-regulates quantity by destabilization”	SMAD2	phosphorylation
SRC	up-regulates	ARAF	phosphorylation
SRC	“up-regulates activity”	ARAF	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 144 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	8	56.4×	1e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	49.8×	3e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	43.5×	1e-08
Activation of BH3-only proteins	8	36.8×	3e-09
Constitutive Signaling by EGFRvIII	5	33.0×	7e-06
Signaling by ERBB2 ECD mutants	5	31.1×	1e-05
Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants	5	26.4×	2e-05
RAF activation	8	24.9×	8e-08

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of nitric oxide biosynthetic process	6	21.9×	4e-04
protein targeting	6	17.6×	7e-04
ERK1 and ERK2 cascade	6	15.3×	7e-04
thymus development	5	13.5×	3e-03
Ras protein signal transduction	7	11.5×	7e-04
epidermal growth factor receptor signaling pathway	5	9.9×	9e-03
regulation of protein localization	6	9.9×	3e-03
MAPK cascade	8	9.8×	7e-04

Disease & clinical

Cancer significance

From CIViC — curated cancer-variant interpretation:

ARAF has recently become increasingly considered for its oncogenic potential. Its potential as a target for informing clinical action was demonstrated by a single case of advanced lung adenocarcinoma harboring an S214C mutation that, when treated with sorafenib, acheived near-complete clinical remission. This finding has brought new focus on ARAF as a marker that should be assayed for in cancer treatment.

From intOGen — cancer-driver classification: activating (oncogene-like) across 3 cancer types — CHOL, LUAD, SCLC.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	3
Uncertain significance	42
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
3391953	GRCh37/hg19 Xp11.3-11.23(chrX:44182604-47607117)x1	Pathogenic
488014	Single allele	Pathogenic
59265	GRCh38/hg38 Xp11.4-11.23(chrX:41434043-47880733)x1	Pathogenic
148196	GRCh38/hg38 Xp11.3-11.23(chrX:44765664-49343053)x3	Likely pathogenic
155022	GRCh38/hg38 Xp11.3-11.23(chrX:44632305-47607180)x2	Likely pathogenic
442436	GRCh37/hg19 Xp11.3-11.23(chrX:46326268-48801984)x2	Likely pathogenic

SpliceAI

2588 predictions. Top by Δscore:

Variant	Effect	Δscore
X:47561248:ACAGG:A	donor_loss	1.0000
X:47561249:CAGG:C	donor_loss	1.0000
X:47561250:AGGT:A	donor_loss	1.0000
X:47561251:GGT:G	donor_loss	1.0000
X:47561253:T:A	donor_loss	1.0000
X:47563326:AGGG:A	donor_gain	1.0000
X:47563326:AGGGG:A	donor_loss	1.0000
X:47563327:GGG:G	donor_gain	1.0000
X:47563327:GGGG:G	donor_gain	1.0000
X:47563328:GG:G	donor_gain	1.0000
X:47563328:GGG:G	donor_gain	1.0000
X:47563329:GG:G	donor_gain	1.0000
X:47563329:GGTG:G	donor_loss	1.0000
X:47563330:G:GG	donor_gain	1.0000
X:47563330:G:T	donor_loss	1.0000
X:47563331:T:G	donor_loss	1.0000
X:47564784:A:AG	acceptor_gain	1.0000
X:47564784:AT:A	acceptor_gain	1.0000
X:47564785:T:G	acceptor_gain	1.0000
X:47564785:T:TA	acceptor_gain	1.0000
X:47564792:T:TA	acceptor_gain	1.0000
X:47564792:TGCA:T	acceptor_loss	1.0000
X:47564793:GCA:G	acceptor_loss	1.0000
X:47564794:CA:C	acceptor_loss	1.0000
X:47564795:A:AG	acceptor_gain	1.0000
X:47564795:AGAC:A	acceptor_gain	1.0000
X:47564796:G:GA	acceptor_gain	1.0000
X:47564796:GA:G	acceptor_gain	1.0000
X:47564796:GAC:G	acceptor_gain	1.0000
X:47564796:GACG:G	acceptor_gain	1.0000

AlphaMissense

3964 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:47563041:T:C	L25P	1.000
X:47563263:T:C	L45P	1.000
X:47563275:T:C	L49P	1.000
X:47563290:T:C	L54P	1.000
X:47563306:T:G	C59W	1.000
X:47563311:T:A	V61D	1.000
X:47564816:T:A	W74R	1.000
X:47564816:T:C	W74R	1.000
X:47564818:G:C	W74C	1.000
X:47564818:G:T	W74C	1.000
X:47564853:T:C	L86P	1.000
X:47564859:T:A	V88D	1.000
X:47564891:C:G	H99D	1.000
X:47565015:T:A	C112S	1.000
X:47565015:T:C	C112R	1.000
X:47565016:G:A	C112Y	1.000
X:47565016:G:C	C112S	1.000
X:47565016:G:T	C112F	1.000
X:47565017:T:G	C112W	1.000
X:47565024:T:A	C115S	1.000
X:47565024:T:C	C115R	1.000
X:47565025:G:A	C115Y	1.000
X:47565025:G:C	C115S	1.000
X:47565025:G:T	C115F	1.000
X:47565026:C:G	C115W	1.000
X:47565046:G:A	G122D	1.000
X:47565054:T:A	C125S	1.000
X:47565054:T:C	C125R	1.000
X:47565055:G:A	C125Y	1.000
X:47565055:G:C	C125S	1.000

dbSNP variants (sampled 300 via entrez): RS1000473726 (X:47563174 A>T), RS1000930549 (X:47572048 C>T), RS1001882020 (X:47565192 C>T), RS1002603457 (X:47570626 A>G), RS1002763115 (X:47571441 CCCG>C), RS1002985476 (X:47560324 T>C), RS1003199495 (X:47568310 T>G), RS1004488370 (X:47571190 C>T), RS1004838768 (X:47571600 T>C), RS1004944860 (X:47562879 A>G), RS1005375306 (X:47563955 G>T), RS1005398963 (X:47564512 T>G), RS1006145711 (X:47570582 A>G), RS10066 (X:47572140 G>A), RS1006792090 (X:47566191 A>G)

Disease associations

OMIM: gene MIM:311010 | disease phenotypes: MIM:181500, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
diffuse lymphatic malformation	Limited	Autosomal dominant

Mondo (3): schizophrenia (MONDO:0005090), autism (MONDO:0005260), diffuse lymphatic malformation (MONDO:0015408)

Orphanet (1): NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0100753	Schizophrenia
HP:0000717	Autism

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1169596 (SINGLE PROTEIN), CHEMBL3559685 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

9 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 118,766 (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
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL4583691	NAPORAFENIB	3	1,168
CHEMBL1738757	REBASTINIB	2	1,478
CHEMBL206834	BAFETINIB	2	1,024
CHEMBL3977543	BELVARAFENIB	2	659
CHEMBL5095099	EXARAFENIB	2	45
CHEMBL3577124	LY-3009120	1	198

Clinical evidence (CIViC)

Drug × variant × indication: 3 predictive associations from 4 curated evidence items; also 3 oncogenic.

Variant	Therapy	Indication	Effect	Level	CIViC
ARAF S214C	Sorafenib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC C	EID17 +1
BRAF V600E AND ARAF S490T	Irinotecan + Vemurafenib + Cetuximab	Colorectal Cancer	Resistance	CIViC C	EID1905
ARAF S214C	Trametinib	Lung Non-small Cell Carcinoma	Sensitivity/Response	CIViC D	EID41

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — RAF family

Most potent curated ligand interactions (3 total), top 3:

Ligand	Action	Affinity	Parameter
exarafenib	Inhibition	8.62	pIC50
lifirafenib	Inhibition	8.25	pIC50
LY3009120	Inhibition	7.36	pIC50

Binding affinities (BindingDB)

2 measured of 2 human assays (500 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-(3,3-dimethylbutyl)-3-[4-fluoro-3-[2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl]phenyl]urea	IC50	20 nM	US-9187474: Raf inhibitor compounds
1-(3-fluoro-3-methylbutyl)-3-[2-fluoro-4-methyl-5-[2-methyl-7-(methylamino)-1,6-naphthyridin-3-yl]phenyl]urea	IC50	170 nM	US-9187474: Raf inhibitor compounds

ChEMBL bioactivities

46 potent at pChembl≥5 of 48 total, top 43 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL4466555
8.92	IC50	1.2	nM	LY-3009120
8.68	IC50	2.1	nM	VEMURAFENIB
8.62	IC50	2.4	nM	EXARAFENIB
8.25	IC50	5.6	nM	CHEMBL4207519
8.15	IC50	7.1	nM	SORAFENIB
8.07	IC50	8.6	nM	CHEMBL4438236
7.92	IC50	12	nM	SORAFENIB
7.84	IC50	14.6	nM	GW305074X
7.75	IC50	17.8	nM	CHEMBL4060057
7.60	IC50	25.3	nM	CHEMBL4075036
7.60	IC50	25.3	nM	CHEMBL4282601
7.58	IC50	26	nM	DABRAFENIB
7.52	IC50	30.1	nM	CHEMBL4289810
7.51	IC50	31	nM	CHEMBL3891833
7.47	IC50	34.1	nM	CHEMBL4087837
7.45	IC50	35.7	nM	CHEMBL4436132
7.42	IC50	37.6	nM	CHEMBL4080362
7.39	IC50	40.7	nM	CHEMBL4104590
7.38	IC50	42.2	nM	CHEMBL4085294
7.36	IC50	44	nM	LY-3009120
7.36	IC50	43.4	nM	CHEMBL4066939
7.33	Kd	47	nM	DABRAFENIB
7.33	IC50	46.9	nM	CHEMBL4082425
7.28	IC50	52.4	nM	CHEMBL4586402
7.24	IC50	57.4	nM	CHEMBL4060531
6.92	IC50	120	nM	CHEMBL3963155
6.82	IC50	152	nM	BELVARAFENIB
6.74	IC50	183	nM	CHEMBL4542639
6.71	IC50	194	nM	CHEMBL4101882
6.68	IC50	211	nM	CHEMBL4447617
6.64	IC50	230	nM	REBASTINIB
6.56	IC50	276	nM	CHEMBL4436132
6.38	IC50	414	nM	NAPORAFENIB
6.02	IC50	950	nM	VEMURAFENIB
6.00	IC50	1000	nM	CHEMBL3934468
5.95	IC50	1130	nM	VEMURAFENIB
5.87	Kd	1339	nM	CHEMBL5653589
5.67	Kd	2138	nM	VEMURAFENIB
5.67	ED50	2149	nM	CHEMBL5653589
5.54	Kd	2893	nM	BAFETINIB
5.15	IC50	7058	nM	CHEMBL4866102
5.09	Kd	8152	nM	CHEMBL3752910

PubChem BioAssay actives

43 with measured affinity, of 363 total; 32 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
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-(7H-purin-6-yl)cyclopropanecarbonyl]amino]benzamide	1534569: Inhibition of human ARAF using MEK1 as substrate by [gamma-33P]-ATP assay	ic50	0.0010	uM
1-(3,3-dimethylbutyl)-3-[2-fluoro-4-methyl-5-[7-methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl]phenyl]urea	1534638: Inhibition of ARaf (unknown origin)	ic50	0.0012	uM
Vemurafenib	1480958: Inhibition of ARAF (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	0.0021	uM
(3S)-N-[3-[2-[[(2R)-1-hydroxypropan-2-yl]amino]-6-morpholin-4-yl-4-pyridinyl]-4-methylphenyl]-3-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide	2099113: Inhibition of ARAF (unknown origin) by ADP-Glo assay	ic50	0.0024	uM
5-[[(1S,1aR,6bS)-1-[6-(trifluoromethyl)-1H-benzimidazol-2-yl]-1a,6b-dihydro-1H-cyclopropa[b][1]benzofuran-5-yl]oxy]-3,4-dihydro-1H-1,8-naphthyridin-2-one	1380332: Inhibition of ARAF (unknown origin)	ic50	0.0056	uM
Sorafenib	1480958: Inhibition of ARAF (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	0.0071	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclopropanecarbonyl]amino]benzamide	1534638: Inhibition of ARaf (unknown origin)	ic50	0.0086	uM
(3Z)-3-[(3,5-dibromo-4-hydroxyphenyl)methylidene]-5-iodo-1H-indol-2-one	1531585: Inhibition of human ARAF using MEK1 as substrate by [gamma-33P]-ATP assay	ic50	0.0146	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[6-(methylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480958: Inhibition of ARAF (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	0.0178	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[6-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480958: Inhibition of ARAF (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	0.0253	uM
N-[3-chloro-4-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[6-[3-(4-methylpiperazin-1-yl)propylamino]pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1408848: Inhibition of ARAF (unknown origin)	ic50	0.0253	uM
Dabrafenib	1226910: Competitive binding affinity to ARAF in human A375 cells after 15 mins in presence of ATP analogue	ic50	0.0260	uM
N-[3-chloro-4-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[2-[2-(4-methylpiperazin-1-yl)ethylamino]pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1408852: Inhibition of ARAF (unknown origin) after 20 mins in presence of 33P-gamma-ATP by hotspot kinase	ic50	0.0301	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-3-[[1-[6-[3-(dimethylamino)propylamino]pyrimidin-4-yl]cyclopropanecarbonyl]amino]-4-methylbenzamide	1480958: Inhibition of ARAF (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	0.0341	uM
4-methyl-N-[4-[(1-methylpiperidin-4-yl)methoxy]-3-(trifluoromethyl)phenyl]-3-[[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclopropanecarbonyl]amino]benzamide	1534638: Inhibition of ARaf (unknown origin)	ic50	0.0357	uM
4-methyl-3-[[1-[6-(methylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]-N-[4-[(1-methylpiperidin-4-yl)methoxy]-3-(trifluoromethyl)phenyl]benzamide	1480958: Inhibition of ARAF (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	0.0376	uM
4-methyl-3-[[1-[6-(methylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]-N-[4-(3-morpholin-4-ylpropoxy)-3-(trifluoromethyl)phenyl]benzamide	1480958: Inhibition of ARAF (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	0.0407	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[6-[(1-methylpiperidin-4-yl)methylamino]pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480958: Inhibition of ARAF (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	0.0422	uM
4-methyl-3-[[1-[6-(methylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]-N-[4-(1-methylpiperidin-4-yl)oxy-3-(trifluoromethyl)phenyl]benzamide	1480958: Inhibition of ARAF (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	0.0434	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[6-(2-pyrrolidin-1-ylethylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480958: Inhibition of ARAF (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	0.0469	uM
4-methyl-N-[4-(1-methylpiperidin-4-yl)oxy-3-(trifluoromethyl)phenyl]-3-[[1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)cyclopropanecarbonyl]amino]benzamide	1534638: Inhibition of ARaf (unknown origin)	ic50	0.0524	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[6-(2-piperidin-1-ylethylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480958: Inhibition of ARAF (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	0.0574	uM
4-amino-N-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide	2116944: Inhibition of ARAF (unknown origin)	ic50	0.1520	uM
N-[4-[4-amino-3-(methylcarbamoyl)phenoxy]phenyl]-4-chloro-3-(trifluoromethyl)benzamide	1594028: Inhibition of human ARAF using human His6-tagged MEK1 (K97R) as substrate preincubated for 20 mins followed by [33P-gamma]ATP addition and measured after 2 hrs by filter-binding assay	ic50	0.1830	uM
N-[4-chloro-3-(trifluoromethyl)phenyl]-4-methyl-3-[[1-[2-(methylamino)pyrimidin-4-yl]cyclopropanecarbonyl]amino]benzamide	1480958: Inhibition of ARAF (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	0.1940	uM
2-amino-5-[4-[(4-methoxybenzoyl)amino]phenoxy]-N-methylbenzamide	1594028: Inhibition of human ARAF using human His6-tagged MEK1 (K97R) as substrate preincubated for 20 mins followed by [33P-gamma]ATP addition and measured after 2 hrs by filter-binding assay	ic50	0.2110	uM
4-[4-[(3-tert-butyl-1-quinolin-6-ylpyrazol-5-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	2168226: Inhibition of human ARAF preincubated for 2 hrs followed by ATP addition and measured every 2 mins for 2.5 hrs by spectrophotometric analysis	ic50	0.2300	uM
N-[3-[2-(2-hydroxyethoxy)-6-morpholin-4-yl-4-pyridinyl]-4-methylphenyl]-2-(trifluoromethyl)pyridine-4-carboxamide	2116944: Inhibition of ARAF (unknown origin)	ic50	0.4140	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147878: Binding affinity to human ARAF incubated for 45 mins by Kinobead based pull down assay	kd	1.3388	uM
4-[[(3S)-3-(dimethylamino)pyrrolidin-1-yl]methyl]-N-[4-methyl-3-[(4-pyrimidin-5-ylpyrimidin-2-yl)amino]phenyl]-3-(trifluoromethyl)benzamide	1424915: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	2.8930	uM
6-(3-phenylmethoxyphenyl)-5-pyrimidin-4-ylimidazo[2,1-b][1,3]thiazole	1772919: Inhibition of A-RAF (unknown origin) incubated for 40 mins in presence of Mg/ATP mix by [gamma p33]-ATP based scintillation counting method	ic50	7.0580	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147878: Binding affinity to human ARAF incubated for 45 mins by Kinobead based pull down assay	kd	8.1519	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, affects cotreatment, increases expression	2
Resveratrol	affects reaction, increases activity, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases methylation	2
Dexamethasone	affects binding, decreases reaction, increases reaction, affects cotreatment, increases expression	2
Estradiol	increases activity, increases expression, decreases reaction	2
Valproic Acid	increases expression, increases methylation	2
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	affects expression	1
aflatoxin B2	decreases methylation	1
coumarin	affects phosphorylation	1
avobenzone	increases expression	1
abrine	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Irinotecan	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzophenoneidum	increases expression	1
Caffeine	decreases phosphorylation	1
Carbamazepine	affects expression	1
Diazinon	increases methylation	1
Diclofenac	affects expression	1
Environmental Pollutants	affects expression	1
Fenbendazole	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Lead	decreases expression	1
Methylnitronitrosoguanidine	increases expression	1

ChEMBL screening assays

92 unique, capped per target: 92 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1176703	Binding	Inhibition of ARAF at 10 uM	Synthesis and structure-activity relationship of 6-arylureido-3-pyrrol-2-ylmethylideneindolin-2-one derivatives as potent receptor tyrosine kinase inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

18 cell lines: 15 cancer cell line, 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2RX	Abcam HEK293T ARAF KO	Transformed cell line	Female
CVCL_B8BE	Abcam HCT 116 ARAF KO	Cancer cell line	Male
CVCL_B8SI	Abcam MCF-7 ARAF KO	Cancer cell line	Female
CVCL_B9DH	Abcam A-549 ARAF KO	Cancer cell line	Male
CVCL_D7KA	Ubigene A-549 ARAF KO	Cancer cell line	Male
CVCL_D8HF	Ubigene HCT 116 ARAF KO	Cancer cell line	Male
CVCL_D8ZD	Ubigene HEK293 ARAF KO	Transformed cell line	Female
CVCL_D9XR	Ubigene HeLa ARAF KO	Cancer cell line	Female
CVCL_SD15	HAP1 ARAF (-) 1	Cancer cell line	Male
CVCL_SD16	HAP1 ARAF (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety