RAF1

Summary

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

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

Source: NCBI Gene 5894 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Noonan syndrome (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 25
• Clinical variants (ClinVar): 1,375 total — 13 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes — 31 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002880

Identifiers

Gene identifiers

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

Gene structure

Transcript identifiers

Ensembl transcripts: 102 — 49 protein_coding, 27 retained_intron, 26 nonsense_mediated_decay

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

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

CCDS: CCDS2612, CCDS87047, CCDS93217

Canonical transcript exons

ENST00000251849 — 17 exons

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

Expression profiles

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

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

FANTOM5 promoters (5 alternative TSS)

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

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	98.17	gold quality
muscle of leg	UBERON:0001383	98.00	gold quality
ventricular zone	UBERON:0003053	97.85	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.67	gold quality
muscle organ	UBERON:0001630	97.62	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.53	gold quality
ganglionic eminence	UBERON:0004023	97.48	gold quality
blood	UBERON:0000178	97.18	gold quality
cortical plate	UBERON:0005343	97.08	gold quality
right coronary artery	UBERON:0001625	96.91	gold quality
heart left ventricle	UBERON:0002084	96.84	gold quality
right atrium auricular region	UBERON:0006631	96.83	gold quality
skeletal muscle tissue	UBERON:0001134	96.80	gold quality
popliteal artery	UBERON:0002250	96.79	gold quality
cardiac ventricle	UBERON:0002082	96.78	gold quality
left ovary	UBERON:0002119	96.78	gold quality
tibial artery	UBERON:0007610	96.78	gold quality
right ovary	UBERON:0002118	96.77	gold quality
cerebellar hemisphere	UBERON:0002245	96.76	gold quality
cardiac atrium	UBERON:0002081	96.73	gold quality
cerebellar cortex	UBERON:0002129	96.73	gold quality
descending thoracic aorta	UBERON:0002345	96.72	gold quality
vastus lateralis	UBERON:0001379	96.70	gold quality
apex of heart	UBERON:0002098	96.70	gold quality
quadriceps femoris	UBERON:0001377	96.69	gold quality
heart	UBERON:0000948	96.64	gold quality
skin of leg	UBERON:0001511	96.64	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.62	gold quality
aorta	UBERON:0000947	96.58	gold quality
left uterine tube	UBERON:0001303	96.55	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

79 targeting RAF1, 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-6077	99.99	68.04	2299
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-4492	99.87	68.25	3611

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

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

Cross-species orthologs

5 orthologs

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

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

Protein

Protein identifiers

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

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

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

UniProt curated annotations — full annotation on UniProt →

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

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

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

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

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

Disease relevance. Noonan syndrome 5 (NS5) [MIM:611553] A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. The disease is caused by variants affecting the gene represented in this entry. LEOPARD syndrome 2 (LPRD2) [MIM:611554] A disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness. The disease is caused by variants affecting the gene represented in this entry. Cardiomyopathy, dilated, 1NN (CMD1NN) [MIM:615916] A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. The disease is caused by variants affecting the gene represented in this entry.

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

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

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

Isoforms (2)

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

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

Domains & families (InterPro)

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

Pfam: PF00130, PF02196, PF07714

Enzyme classification (BRENDA):

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

Substrate kinetics (BRENDA)

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

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

Catalyzed reactions (Rhea), 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 (115 total): sequence variant 24, strand 21, modified residue 20, helix 12, binding site 10, turn 8, mutagenesis site 7, compositionally biased region 3, domain 2, region of interest 2, sequence conflict 2, chain 1, zinc finger region 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

76 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3IQU	X-RAY DIFFRACTION	1.05
3IQJ	X-RAY DIFFRACTION	1.15
3IQV	X-RAY DIFFRACTION	1.2
6VJJ	X-RAY DIFFRACTION	1.4
8ATS	X-RAY DIFFRACTION	1.4
9EW1	X-RAY DIFFRACTION	1.4
9EW3	X-RAY DIFFRACTION	1.4
8AV0	X-RAY DIFFRACTION	1.5
9EW5	X-RAY DIFFRACTION	1.5
9S2J	X-RAY DIFFRACTION	1.5
9S2P	X-RAY DIFFRACTION	1.5
8A68	X-RAY DIFFRACTION	1.6
8A6F	X-RAY DIFFRACTION	1.6
8A6H	X-RAY DIFFRACTION	1.6
9EW4	X-RAY DIFFRACTION	1.6
8JNB	X-RAY DIFFRACTION	1.62
8T74	X-RAY DIFFRACTION	1.65
9S2I	X-RAY DIFFRACTION	1.67
9YGS	X-RAY DIFFRACTION	1.68
4IEA	X-RAY DIFFRACTION	1.7
8ATR	X-RAY DIFFRACTION	1.7
8JNA	X-RAY DIFFRACTION	1.7
8S42	X-RAY DIFFRACTION	1.7
9EW7	X-RAY DIFFRACTION	1.8
9S2O	X-RAY DIFFRACTION	1.8
9S2L	X-RAY DIFFRACTION	1.85
9S2N	X-RAY DIFFRACTION	1.85
1C1Y	X-RAY DIFFRACTION	1.9
3KUC	X-RAY DIFFRACTION	1.92
4FJ3	X-RAY DIFFRACTION	1.95

Predicted structure (AlphaFold)

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

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): 468 (proton acceptor)

Ligand- & substrate-binding residues (10): 139; 152; 155; 165; 168; 173; 176; 184; 355–363; 375

Post-translational modifications (20): 29, 43, 252, 259, 268, 269, 289, 296, 301, 338, 339, 340, 341, 471, 491, 494, 499, 563, 621, 642

Mutagenesis-validated functional residues (7):

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

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-392517	Rap1 signalling
R-HSA-430116	GP1b-IX-V activation signalling
R-HSA-5621575	CD209 (DC-SIGN) signaling
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-9732724	IFNG signaling activates MAPKs

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

GO Biological Process (34): MAPK cascade (GO:0000165), protein phosphorylation (GO:0006468), apoptotic process (GO:0006915), signal transduction (GO:0007165), negative regulation of cell population proliferation (GO:0008285), insulin receptor signaling pathway (GO:0008286), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), Schwann cell development (GO:0014044), thyroid gland development (GO:0030878), negative regulation of protein-containing complex assembly (GO:0031333), positive regulation of peptidyl-serine phosphorylation (GO:0033138), somatic stem cell population maintenance (GO:0035019), regulation of Rho protein signal transduction (GO:0035023), insulin secretion involved in cellular response to glucose stimulus (GO:0035773), response to muscle stretch (GO:0035994), ERBB2-ERBB3 signaling pathway (GO:0038133), wound healing (GO:0042060), myelination (GO:0042552), regulation of apoptotic process (GO:0042981), negative regulation of apoptotic process (GO:0043066), positive regulation of MAPK cascade (GO:0043410), type B pancreatic cell proliferation (GO:0044342), intermediate filament cytoskeleton organization (GO:0045104), regulation of cell differentiation (GO:0045595), positive regulation of transcription by RNA polymerase II (GO:0045944), insulin-like growth factor receptor signaling pathway (GO:0048009), neurotrophin TRK receptor signaling pathway (GO:0048011), thymus development (GO:0048538), face development (GO:0060324), type II interferon-mediated signaling pathway (GO:0060333), death-inducing signaling complex assembly (GO:0071550), negative regulation of extrinsic apoptotic signaling pathway via death domain receptors (GO:1902042), intracellular glucose homeostasis (GO:0001678), cell differentiation (GO:0030154)

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

GO Cellular Component (9): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), pseudopodium (GO:0031143), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-10 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
cellular anatomical structure	3
cytoplasm	3
apoptotic process	2
protein kinase activity	2
protein binding	2
intracellular signaling cassette	1
phosphorylation	1
protein modification process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to insulin stimulus	1
extrinsic apoptotic signaling pathway	1
Schwann cell differentiation	1
glial cell development	1
endocrine system development	1
gland development	1
regulation of protein-containing complex assembly	1
negative regulation of cellular component organization	1
protein-containing complex assembly	1
positive regulation of protein phosphorylation	1
peptidyl-serine phosphorylation	1
regulation of peptidyl-serine phosphorylation	1
stem cell population maintenance	1
Rho protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
insulin secretion	1
establishment of localization in cell	1
cellular response to glucose stimulus	1
response to mechanical stimulus	1

Protein interactions and networks

STRING

3599 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAF1	HRAS	P01112	986
RAF1	BRAF	P15056	983
RAF1	KSR1	Q8IVT5	982
RAF1	KRAS	P01116	976
RAF1	MAP2K1	Q02750	970
RAF1	YWHAZ	P29213	962
RAF1	RAP1A	P10113	948
RAF1	NRAS	P01111	900
RAF1	PEBP1	P30086	894
RAF1	BAG1	Q99933	876
RAF1	SPRY1	O43609	847
RAF1	ARAF	P07557	803
RAF1	SOS1	Q07889	798
RAF1	GRB2	P29354	777
RAF1	YWHAH	Q04917	774

IntAct

534 interactions, top by confidence:

A	B	Type	Score
HRAS	RAF1	psi-mi:“MI:0915”(physical association)	0.980
RAF1	HRAS	psi-mi:“MI:0407”(direct interaction)	0.980
HRAS	RAF1	psi-mi:“MI:0407”(direct interaction)	0.980
RAF1	HRAS	psi-mi:“MI:0915”(physical association)	0.980
HRAS	RAF1	psi-mi:“MI:0403”(colocalization)	0.980
HRAS	RAF1	psi-mi:“MI:0914”(association)	0.980
RAF1	YWHAZ	psi-mi:“MI:0407”(direct interaction)	0.970
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 (2441): RAF1 (Reconstituted Complex), MAP2K1 (Affinity Capture-Western), MAP2K2 (Affinity Capture-Western), MAPK3 (Affinity Capture-Western), MAPK1 (Affinity Capture-Western), MAPK3 (Biochemical Activity), MAPK1 (Biochemical Activity), AKT1 (Affinity Capture-Western), RAF1 (Affinity Capture-Western), RAF1 (Affinity Capture-Western), RAF1 (Affinity Capture-Western), RAF1 (Affinity Capture-Western), RB1 (Affinity Capture-Western), RAF1 (Biochemical Activity), RANBP9 (Two-hybrid)

ESM2 similar proteins: A2VDU3, A7E3S4, A8XJW8, E9PUQ8, F1QGZ6, O35346, O43318, O54748, P04049, P05625, P09560, P0C8E4, P11345, P11346, P27966, P33886, P34152, P34908, P42331, Q00944, Q04982, Q05397, Q07192, Q07292, Q08BR4, Q16760, Q21029, Q3UVC0, Q56R14, Q5R5M7, Q5RFL3, Q5U2Z7, Q61083, Q61084, Q61097, Q61UC4, Q62073, Q69Z98, Q6GPK9, 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

112 interactions.

A	Effect	B	Mechanism
2-chloro-5-(2-phenyl-5-pyridin-4-yl-1H-imidazol-4-yl)phenol	down-regulates	RAF1	“chemical inhibition”
RAF1	down-regulates	MAP3K5	binding
PKN1	up-regulates	RAF1	phosphorylation
CNKSR2	up-regulates	RAF1	binding
WDR83	up-regulates	RAF1	binding
RAF1	down-regulates	STK3	binding
MAPK3	down-regulates	RAF1	phosphorylation
CNKSR1	up-regulates	RAF1	binding
PPP2CA	up-regulates	RAF1	dephosphorylation
KRAS	up-regulates	RAF1	binding
AKT1	down-regulates	RAF1	phosphorylation
RAF1	down-regulates	BAD	phosphorylation
sorafenib	down-regulates	RAF1	“chemical inhibition”
NRAS	up-regulates	RAF1	relocalization
PAK1	up-regulates	RAF1	phosphorylation
3-(2-cyanopropan-2-yl)-N-[4-methyl-3-[(3-methyl-4-oxo-6-quinazolinyl)amino]phenyl]benzamide	down-regulates	RAF1	“chemical inhibition”
RAF1	down-regulates	STK4	binding
4-methyl-3-[[1-methyl-6-(3-pyridinyl)-4-pyrazolo[3,4-d]pyrimidinyl]amino]-N-[3-(trifluoromethyl)phenyl]benzamide	down-regulates	RAF1	“chemical inhibition”
1-methyl-5-[[2-[5-(trifluoromethyl)-1H-imidazol-2-yl]-4-pyridinyl]oxy]-N-[4-(trifluoromethyl)phenyl]-2-benzimidazolamine	down-regulates	RAF1	“chemical inhibition”
“Raf265 derivative”	down-regulates	RAF1	“chemical inhibition”
regorafenib	down-regulates	RAF1	“chemical inhibition”
“ZM 336372”	down-regulates	RAF1	“chemical inhibition”
AMPK	down-regulates	RAF1	phosphorylation
AMPK	up-regulates	RAF1	phosphorylation
AKT2	“down-regulates activity”	RAF1	phosphorylation
HRAS	up-regulates	RAF1	binding
RAF1	“up-regulates activity”	MAP2K1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 107 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
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	8	72.6×	4e-12
Activation of BAD and translocation to mitochondria	7	72.0×	1e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	63.5×	3e-10
Activation of BH3-only proteins	8	53.7×	6e-11
RAF activation	11	49.9×	4e-14
Signaling by high-kinase activity BRAF mutants	11	47.1×	5e-14
Negative regulation of MAPK pathway	12	43.1×	2e-14
MAP2K and MAPK activation	11	42.4×	1e-13

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	21.8×	6e-04
substantia nigra development	5	21.8×	6e-04
MAPK cascade	11	20.1×	6e-09
ERK1 and ERK2 cascade	5	18.9×	9e-04
Ras protein signal transduction	7	17.1×	8e-05
intracellular protein localization	8	10.0×	4e-04
positive regulation of ERK1 and ERK2 cascade	7	7.1×	5e-03
positive regulation of gene expression	10	4.6×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1375 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	25
Uncertain significance	652
Likely benign	481
Benign	76

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
13957	NM_002880.4(RAF1):c.770C>T (p.Ser257Leu)	Pathogenic
13958	NM_002880.4(RAF1):c.781C>T (p.Pro261Ser)	Pathogenic
13960	NM_002880.4(RAF1):c.1837C>G (p.Leu613Val)	Pathogenic
142296	NM_002880.4(RAF1):c.1808T>C (p.Leu603Pro)	Pathogenic
21342	NM_002880.4(RAF1):c.1472C>T (p.Thr491Ile)	Pathogenic
2883997	NM_002880.4(RAF1):c.786T>G (p.Asn262Lys)	Pathogenic
3338001	NM_002880.4(RAF1):c.784_786dup (p.Asn262_Val263insAsn)	Pathogenic
40601	NM_002880.4(RAF1):c.775T>A (p.Ser259Thr)	Pathogenic
40603	NM_002880.4(RAF1):c.776C>T (p.Ser259Phe)	Pathogenic
40613	NM_002880.4(RAF1):c.1082G>C (p.Gly361Ala)	Pathogenic
426303	NM_002880.4(RAF1):c.778A>C (p.Thr260Pro)	Pathogenic
44633	NM_002880.4(RAF1):c.776C>A (p.Ser259Tyr)	Pathogenic
504514	NM_002880.4(RAF1):c.775T>G (p.Ser259Ala)	Pathogenic
13959	NM_002880.4(RAF1):c.1472C>G (p.Thr491Arg)	Likely pathogenic
165011	NM_002880.4(RAF1):c.285C>G (p.Cys95Trp)	Likely pathogenic
1675069	NM_002880.4(RAF1):c.806C>T (p.Thr269Ile)	Likely pathogenic
181517	NM_002880.4(RAF1):c.785A>T (p.Asn262Ile)	Likely pathogenic
3429947	NM_002880.4(RAF1):c.784A>G (p.Asn262Asp)	Likely pathogenic
373032	NM_002880.4(RAF1):c.433A>C (p.Thr145Pro)	Likely pathogenic
3730878	NM_002880.4(RAF1):c.453C>G (p.Phe151Leu)	Likely pathogenic
395579	GRCh37/hg19 3p25.2(chr3:12633308-12777019)x3	Likely pathogenic
40590	NM_002880.4(RAF1):c.418A>C (p.Asn140His)	Likely pathogenic
40593	NM_002880.4(RAF1):c.483T>G (p.Asn161Lys)	Likely pathogenic
40599	NM_002880.4(RAF1):c.768G>T (p.Arg256Ser)	Likely pathogenic
40600	NM_002880.4(RAF1):c.769T>C (p.Ser257Pro)	Likely pathogenic
40607	NM_002880.4(RAF1):c.788T>G (p.Val263Gly)	Likely pathogenic
4082712	NM_002880.4(RAF1):c.1832A>T (p.His611Leu)	Likely pathogenic
452826	NM_002880.4(RAF1):c.1556T>C (p.Met519Thr)	Likely pathogenic
4539998	NM_002880.4(RAF1):c.1171A>G (p.Arg391Gly)	Likely pathogenic
4689833	NM_002880.4(RAF1):c.1490G>A (p.Ser497Asn)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

4290 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:12584862:C:A	R596S	1.000
3:12584862:C:G	R596S	1.000
3:12584863:C:A	R596M	1.000
3:12584863:C:G	R596T	1.000
3:12584965:C:T	G562D	1.000
3:12584966:C:G	G562R	1.000
3:12585150:G:C	P547R	1.000
3:12585150:G:T	P547H	1.000
3:12585168:A:G	L541P	1.000
3:12585186:C:T	G535D	1.000
3:12585187:C:G	G535R	1.000
3:12585198:A:T	V531D	1.000
3:12585201:T:A	D530V	1.000
3:12585202:C:A	D530Y	1.000
3:12585202:C:G	D530H	1.000
3:12585237:C:G	R518P	1.000
3:12585684:C:A	W511C	1.000
3:12585684:C:G	W511C	1.000
3:12585686:A:G	W511R	1.000
3:12585686:A:T	W511R	1.000
3:12585697:C:T	G507D	1.000
3:12585698:C:G	G507R	1.000
3:12585751:A:G	L489S	1.000
3:12585754:C:T	G488D	1.000
3:12585755:C:G	G488R	1.000
3:12585756:A:C	F487L	1.000
3:12585756:A:T	F487L	1.000
3:12585757:A:G	F487S	1.000
3:12585758:A:G	F487L	1.000
3:12585759:A:C	D486E	1.000

dbSNP variants (sampled 300 via entrez): RS1000003721 (3:12603320 A>C), RS1000030872 (3:12621755 G>T), RS1000031459 (3:12603618 A>G,T), RS1000038307 (3:12631336 C>T), RS1000041336 (3:12655830 G>A,C), RS1000066616 (3:12605884 C>T), RS1000139985 (3:12631588 G>C), RS1000148280 (3:12645217 C>A,G), RS1000220703 (3:12656200 G>C), RS1000239125 (3:12639255 A>T), RS1000417061 (3:12610384 A>G), RS1000439555 (3:12602141 C>T), RS1000441289 (3:12649866 G>T), RS1000466872 (3:12591278 A>C), RS1000482903 (3:12589944 C>T)

Disease associations

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

GenCC curated gene-disease

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

ClinGen Gene-Disease Validity (4)

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

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

Mondo (19): RASopathy (MONDO:0021060), Noonan syndrome 5 (MONDO:0012690), LEOPARD syndrome 2 (MONDO:0012691), dilated cardiomyopathy 1NN (MONDO:0014396), glioma (MONDO:0021042), Noonan syndrome (MONDO:0018997), Noonan syndrome and Noonan-related syndrome (MONDO:0020297), Noonan syndrome with multiple lentigines (MONDO:0007893), Noonan syndrome 1 (MONDO:0008104), familial hypertrophic cardiomyopathy (MONDO:0024573), hypertrophic cardiomyopathy 1 (MONDO:0008647), dilated cardiomyopathy (MONDO:0005021), ventricular tachycardia (MONDO:0005477), trigonitis (MONDO:0001732), Noonan syndrome 3 (MONDO:0012371)

Orphanet (10): RASopathy (Orphanet:536391), Familial isolated dilated cardiomyopathy (Orphanet:154), Noonan syndrome with multiple lentigines (Orphanet:500), Noonan syndrome (Orphanet:648), Glial tumor (Orphanet:182067), Noonan syndrome and Noonan-related syndrome (Orphanet:98733), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Dilated cardiomyopathy (Orphanet:217604), Pituitary stalk interruption syndrome (Orphanet:95496), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0001644	Dilated cardiomyopathy

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST000760_18	Cholesterol, total	4.000000e-09
GCST000960_17	Cardiac hypertrophy	7.000000e-07
GCST002221_35	Cholesterol, total	2.000000e-09
GCST004235_60	Total cholesterol levels	1.000000e-18
GCST005956_72	Waist-to-hip ratio adjusted for BMI	1.000000e-07
GCST005957_11	Waist-to-hip ratio adjusted for BMI (age <50)	9.000000e-06
GCST005958_19	Waist-to-hip ratio adjusted for BMI (age >50)	2.000000e-06
GCST005962_29	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	9.000000e-09
GCST010042_118	Asthma	2.000000e-09
GCST010151_8	Carotid intima media thickness x smoking interaction	8.000000e-06
GCST010242_368	HDL cholesterol levels	2.000000e-10
GCST010796_3490	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-11
GCST010796_3491	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-09
GCST010796_3492	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-11
GCST90020024_1139	A body shape index	7.000000e-14
GCST90020025_1926	Waist-to-hip ratio adjusted for BMI	2.000000e-11
GCST90020025_1929	Waist-to-hip ratio adjusted for BMI	8.000000e-17
GCST90020025_1931	Waist-to-hip ratio adjusted for BMI	1.000000e-16
GCST90020025_1932	Waist-to-hip ratio adjusted for BMI	4.000000e-14
GCST90020026_190	Hip index	2.000000e-12
GCST90020027_159	Waist-hip index	5.000000e-17
GCST90020027_161	Waist-hip index	3.000000e-17
GCST90020027_162	Waist-hip index	2.000000e-14
GCST90020029_1164	Waist circumference adjusted for body mass index	2.000000e-14
GCST90020029_1165	Waist circumference adjusted for body mass index	1.000000e-08

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0004574	total cholesterol measurement
EFO:0002503	cardiac hypertrophy
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0006527	smoking status measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004327	electrocardiography
EFO:0007789	BMI-adjusted waist circumference
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (12)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D056685	Costello Syndrome	C05.660.207.219; C16.131.077.256; C16.320.188
D005910	Glioma	C04.557.465.625.600.380; C04.557.470.670.380; C04.557.580.625.600.380
D044542	LEOPARD Syndrome	C05.660.207.525; C14.240.400.695; C14.280.400.695; C14.280.484.716.525; C16.131.077.525; C16.131.240.400.685; C16.131.621.207.525; C17.800.621.430.530.550.525
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690
D017180	Tachycardia, Ventricular	C14.280.067.845.940; C14.280.123.875.940; C23.550.073.845.940
C535579	Cardiofaciocutaneous syndrome (supp.)
C537117	LEOPARD syndrome, 2 (supp.)
C548083	Noonan Syndrome 5 (supp.)
C537846	Noonan like syndrome (supp.)
C537847	Noonan syndrome 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

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

Molecules with ChEMBL bioactivity

31 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 430,201 (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
CHEMBL1946170	REGORAFENIB	4	12,678
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL255863	NILOTINIB	4	38,627
CHEMBL3348923	TOVORAFENIB	4	834
CHEMBL477772	PAZOPANIB	4	15,540
CHEMBL5416410	DASATINIB	4	655
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL941	IMATINIB	4	111,611
CHEMBL1096380	PLINABULIN	3	686
CHEMBL3264002	AVUTOMETINIB	3	2,208
CHEMBL4583691	NAPORAFENIB	3	1,168
CHEMBL572881	MOTESANIB	3	4,642
CHEMBL103667	DORAMAPIMOD	2	1,681
CHEMBL105442	CI-1040	2	3,936
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1738757	REBASTINIB	2	1,478
CHEMBL1790006	TOLONIUM CHLORIDE	2	7,731
CHEMBL2029988	CEP-32496	2	1,136
CHEMBL3977543	BELVARAFENIB	2
CHEMBL475251	R-406	2
CHEMBL4800252	RISOVALISIB	2
CHEMBL5095099	EXARAFENIB	2
CHEMBL558752	RAF-265	2
CHEMBL5800160	BRIMARAFENIB	2
CHEMBL1614710	OSI-930	1
CHEMBL295316	PLUMBAGIN	1
CHEMBL3577124	LY-3009120	1
CHEMBL4212692	XP-102	1

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 (24 total), top 24:

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

Binding affinities (BindingDB)

2546 measured of 3226 human assays (3407 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

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

ChEMBL bioactivities

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

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

PubChem BioAssay actives

979 with measured affinity, of 2546 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

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

CTD chemical–gene interactions

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

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

ChEMBL screening assays

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

Representative assays (with source publication via chembl_document):

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

Cellosaurus cell lines

41 cell lines: 25 cancer cell line, 12 transformed cell line, 2 induced pluripotent stem cell, 1 finite cell line, 1 telomerase immortalized cell line

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

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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03048084	PHASE4	RECRUITING	Seizure Treatment in Glioma
NCT06625047	PHASE4	COMPLETED	Comparing Telehealth and In-person Assessments in Glioma Patients Receiving Oral Chemotherapy
NCT07486713	PHASE4	RECRUITING	Olutasidenib DDI Study in Patients With IDH1 Mutation Positive Malignancies
NCT00452725	PHASE3	COMPLETED	Effect of MAXOMAT ® on the Growth of Small Children to NOONAN’s Syndrome
NCT01529840	PHASE3	COMPLETED	Somatropin Effect on Linear Growth and Final Height in Subjects With Noonan Syndrome
NCT01529944	PHASE3	COMPLETED	Genetic Testing of Noonan Subjects Previously Treated With Norditropin®. An Extension to Trial GHNOO-1658
NCT01927861	PHASE3	COMPLETED	Investigating the Long-term Efficacy and Safety of Two Doses of NN-220 (Somatropin) in Short Stature Due to Noonan Syndrome
NCT02713945	PHASE3	COMPLETED	Treatment With HMG-COA Reductase Inhibitor of Growth and Bone Abnormalities in Children With Noonan Syndrome
NCT05723835	PHASE3	ACTIVE_NOT_RECRUITING	A Research Study Looking at How Safe Somapacitan is and How Well it Works in Children Who Need Help to Grow - REAL 9
NCT00045968	PHASE3	UNKNOWN	Study of a Drug [DCVax®-L] to Treat Newly Diagnosed GBM Brain Cancer
NCT00256425	PHASE3	UNKNOWN	Cognitive Rehabilitation of Glioma Patients
NCT01479686	PHASE3	COMPLETED	iMRI Guided Resection in Cerebral Glioma Surgery
NCT01502280	PHASE3	COMPLETED	Fluorescence-guided Surgery for Low- and High-grade Gliomas
NCT01655927	PHASE3	UNKNOWN	Efficacy of Tranexamic Acid in Brain Tumor Resections
NCT02363075	PHASE3	UNKNOWN	Dexamfetamine Sulphate in Patients With Glioma Suffering From Severe Asthenia
NCT03149575	PHASE3	TERMINATED	VAL-083 Phase 3 Study in Temozolomide-Avastin (Bevacizumab) Recurrent GBM
NCT03722355	PHASE3	COMPLETED	Hyperfractionated RT With BCNU Versus Conventional RT With BCNU for Supratentorial Malignant Glioma
NCT04164901	PHASE3	ACTIVE_NOT_RECRUITING	Study of Vorasidenib (AG-881) in Participants With Residual or Recurrent Grade 2 Glioma With an IDH1 or IDH2 Mutation (INDIGO)
NCT05303519	PHASE3	RECRUITING	SIGMA (Safusidenib in IDH1 Mutant Glioma Maintenance)
NCT05512403	PHASE3	RECRUITING	Evaluation of Diagnostic Performances of 18F-FDOPA PET KInetics
NCT05580562	PHASE3	RECRUITING	ONC201 in H3 K27M-mutant Diffuse Glioma Following Radiotherapy (the ACTION Study)
NCT06330337	PHASE3	RECRUITING	Effect of Electroacupuncture Combined With Paclitaxel Clinical Efficacy of Patients With Recurrence of High-grade Glioma
NCT06496971	PHASE3	RECRUITING	A Prospective Pivotal Study to Evaluate the Efficacy and Safety of Avastin® Bevacizumab (BEV) With or Without Microbubble-mediated Focused Ultrasound (FUS-MB) Using NaviFUS System in Recurrent Glioblastoma Multiforme Patients
NCT06750458	PHASE3	NOT_YET_RECRUITING	Dapagliflozin Versus Dexamethasone Role in Pre-operative Management of Non- Diabetic Brain Tumor Patients
NCT00351221	PHASE2	TERMINATED	Research Study Using Recombinant Human Insulin-Like Growth Factor-1/Recombinant Human Insulin-Like Growth Factor Binding Protein-3 for Children With Noonan Syndrome
NCT06555237	PHASE2	RECRUITING	MEK Inhibitors for the Treatment of Hypertrophic Cardiomyopathy in Patients With RASopathies
NCT06668805	PHASE2	RECRUITING	A Study of Vosoritide in Children With Noonan Syndrome With Inadequate Growth During or After Human Growth Hormone Treatment
NCT00047879	PHASE2	COMPLETED	Phase II Trial of Peginterferon Alpha-2b and Thalidomide in Adults With Recurrent Gliomas
NCT00107003	PHASE2	COMPLETED	GW572016 to Treat Recurrent Malignant Brain Tumors
NCT00108069	PHASE2	COMPLETED	Tamoxifen and Bortezomib to Treat Recurrent Brain Tumors
NCT00147160	PHASE2	COMPLETED	Phase II Cisplatin + Temozolomide in Malignant Glial Tumours in Children and Adolescents
NCT00165360	PHASE2	COMPLETED	Prolonged Daily Temozolomide for Low-Grade Glioma
NCT00200161	PHASE2	COMPLETED	Temozolomide & RT Followed by Dose Dense vs Temozolomide & Retinoic Acid in Pts w/Glioblastoma
NCT00213278	PHASE2	COMPLETED	Phase 2 Study of Vinblastine in Children With Recurrent or Refractory Low Grade Glioma
NCT00350727	PHASE2	COMPLETED	Pazopanib In Combination With Lapatinib In Adult Patients With Relapsed Malignant Glioma
NCT00360828	PHASE2	TERMINATED	Phase II Study of Irinotecan HCI for Recurrent Anaplastic Astrocytomas, Mixed Malignant Gliomas, and Oligodendrogliomas
NCT00389090	PHASE2	TERMINATED	A Phase II Study of Temozolomide and O6-Benzylguanine (O6-BG) in Patients With Temozolomide-Resistant Anaplastic Glioma
NCT00392171	PHASE2	COMPLETED	The Effects of Continuous 28-day (28/28) Temozolomide Chemotherapy in Subjects With Recurrent Malignant Glioma Who Have Failed the Conventional 5-day (5/28) Treatment (P04601)
NCT00404495	PHASE2	COMPLETED	Combination of Irinotecan and Temozolomide in Children With Brain Tumors.
NCT00409214	PHASE2	COMPLETED	Phase IIa Safety and Light Dose-escalation Study in Patients With Primary or Recurrent/High-grade Glioma Using the Litx™ System to Confirm the Zone of Tumor Destruction During the Intraoperative Treatment of Glioma