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Raf-1 proto-oncogene, serine/threonine kinase

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Target not currently curated in GtoImmuPdb

Target id: 2184

Nomenclature: Raf-1 proto-oncogene, serine/threonine kinase

Abbreviated Name: c-Raf

Family: RAF family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 648 3p25.2 RAF1 Raf-1 proto-oncogene, serine/threonine kinase
Mouse - 648 6 53.62 cM Raf1 v-raf-leukemia viral oncogene 1
Rat - 648 4q42 Raf1 Raf-1 proto-oncogene, serine/threonine kinase
Previous and Unofficial Names Click here for help
Raf-1 proto-oncogene | RAF proto-oncogene serine/threonine-protein kinase
Database Links Click here for help
Alphafold P04049 (Hs), Q99N57 (Mm), P11345 (Rn)
BRENDA 2.7.11.1
ChEMBL Target CHEMBL1906 (Hs), CHEMBL3804748 (Mm)
DrugBank Target P04049 (Hs)
Ensembl Gene ENSG00000132155 (Hs), ENSMUSG00000000441 (Mm), ENSRNOG00000010153 (Rn)
Entrez Gene 5894 (Hs), 110157 (Mm), 24703 (Rn)
Human Protein Atlas ENSG00000132155 (Hs)
KEGG Enzyme 2.7.11.1
KEGG Gene hsa:5894 (Hs), mmu:110157 (Mm), rno:24703 (Rn)
OMIM 164760 (Hs)
Orphanet ORPHA138722 (Hs)
Pharos P04049 (Hs)
RefSeq Nucleotide NM_002880 (Hs), NM_029780 (Mm), NM_012639 (Rn)
RefSeq Protein NP_002871 (Hs), NP_084056 (Mm), NP_036771 (Rn)
UniProtKB P04049 (Hs), Q99N57 (Mm), P11345 (Rn)
Wikipedia RAF1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of c-raf (raf-1).
PDB Id:  3OMV
Resolution:  4.0Å
Species:  Human
References:  15
Enzyme Reaction Click here for help
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
TAK-632 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 9.3 pKd 19
⤷ pKd 9.3 (Kd 5.2x10-10 M) [19]
Description: Dissociation constant determined by Surface Plasmon Resonance.
naporafenib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.4 pKd 22
⤷ pKd 8.4 (Kd 3.6x10-9 M) [22]
Description: Binding affinity determined using the KinomeScan® platform.
agerafenib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pKd 24
⤷ pKd 7.4 (Kd 3.9x10-8 M) [24]
brimarafenib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.7 pIC50 29
⤷ pIC50 9.7 (IC50 1.9x10-10 M) [29]
Description: Inhibition of WT CRAF
L779450 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.9 pIC50 30
⤷ pIC50 8.9 (IC50 1.4x10-9 M) [30]
TAK-632 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 8.9 pIC50 19
⤷ pIC50 8.9 (IC50 1.4x10-9 M) [19]
Description: Biochemical enzyme inhibition assay.
SB590885 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.8 pIC50 18
⤷ pIC50 8.8 (IC50 1.72x10-9 M) [18]
Description: In a cell-free assay
exarafenib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition >8.0 – 8.9 pIC50 7,17
⤷ pIC50 8.9 (IC50 1.4x10-9 M) [7]
pIC50 >8.0 (IC50 <1x10-8 M) [17]
Description: Inhibition potency vs. RAF1 was determined in a proprietary ADP-Glo assay
tinlorafenib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.4 pIC50 6
⤷ pIC50 8.4 (IC50 4.1x10-9 M) [6]
belvarafenib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.3 pIC50 3
⤷ pIC50 8.3 (IC50 5x10-9 M) [3]
sorafenib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 8.2 pIC50 26
⤷ pIC50 8.2 (IC50 6x10-9 M) [26]
CCT241161 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.2 pIC50 13
⤷ pIC50 8.2 (IC50 6x10-9 M) [13]
GW5074 Small molecule or natural product Primary target of this compound Hs Inhibition 8.1 pIC50 8
⤷ pIC50 8.1 (IC50 9x10-9 M) [8]
CCT196969 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.0 pIC50 13
⤷ pIC50 8.0 (IC50 1x10-8 M) [13]
RIPK3 inhibitor 18 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 8.0 pIC50 14
⤷ pIC50 8.0 (IC50 1.1x10-8 M) [14]
LY3009120 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.8 pIC50 21
⤷ pIC50 7.8 (IC50 1.5x10-8 M) [21]
plixorafenib Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.6 pIC50 28
⤷ pIC50 7.6 (IC50 2.3x10-8 M) [28]
OSI-930 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 7.4 pIC50 12
⤷ pIC50 7.4 (IC50 4.1x10-8 M) [12]
ZM336372 Small molecule or natural product Hs Inhibition 7.2 – 7.5 pIC50 4,10
⤷ pIC50 7.2 – 7.5 (IC50 7x10-8 – 3.1x10-8 M) [4,10]
avutometinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pIC50 2
⤷ pIC50 7.3 (IC50 5.6x10-8 M) [2]
balamapimod Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 6.9 pIC50 5
⤷ pIC50 6.9 (IC50 1.14x10-7 M) [5]
Description: Measuring c-Raf mediated activation of MEK and phosphorylation of MEK substrate.
vemurafenib Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.4 – 7.3 pIC50 21,25
⤷ pIC50 6.4 – 7.3 (IC50 4.14x10-7 – 4.8x10-8 M) [21,25]
DiscoveRx KINOMEscan® screen Click here for help
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 9,27
Key to terms and symbols Click column headers to sort
Target used in screen: RAF1
Ligand Sp. Type Action Value Parameter
GDC-0879 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 8.2 pKd
PD-173955 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.6 pKd
PLX-4720 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.8 pKd
sorafenib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 6.6 pKd
CHIR-265 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.4 pKd
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.2 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 6.1 pKd
motesanib Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 6.1 pKd
pazopanib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 6.1 pKd
AST-487 Small molecule or natural product Hs Inhibitor Inhibition 6.0 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: 1,11
Key to terms and symbols Click column headers to sort
Target used in screen: c-RAF/RAF1
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
sorafenib Small molecule or natural product Approved drug Ligand has a PDB structure Hs Inhibitor Inhibition 1.4
PKR inhibitor, negative control Small molecule or natural product Hs Inhibitor Inhibition 6.9 2.0 -2.0
pazopanib Small molecule or natural product Approved drug Hs Inhibitor Inhibition 9.4
SB202190 Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 25.8 14.0 1.0
dasatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 39.7
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition 41.1 17.0 3.0
PD 169316 Small molecule or natural product Hs Inhibitor Inhibition 43.9 20.0 13.0
imatinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 47.9
EGFR/ErbB-2 inhibitor Small molecule or natural product Hs Inhibitor Inhibition 61.0 86.0 96.0
p38 MAP kinase inhibitor Small molecule or natural product Hs Inhibitor Inhibition 61.4 33.0 6.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  Immune regulation
Immuno Process:  Cellular signalling
Immuno Process:  Immune system development
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  LEOPARD syndrome 2; LPRD2
Synonyms: LEOPARD syndrome [Orphanet: ORPHA500] [Disease Ontology: DOID:14291]
Disease Ontology: DOID:14291
OMIM: 611554
Orphanet: ORPHA500
References:  20
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human S257L 770C>T 20
Missense Human L613V 1837C>G 20
Disease:  Noonan syndrome 5; NS5
Synonyms: Noonan syndrome [Orphanet: ORPHA648] [Disease Ontology: DOID:3490]
Disease Ontology: DOID:3490
OMIM: 611553
Orphanet: ORPHA648
References:  20,23
Disease:  Pilocytic astrocytoma
Disease Ontology: DOID:4851
Orphanet: ORPHA251612
References:  16

References

Show »

1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

2. Aoki T, Hyohdoh I, Furuichi N, Ozawa S, Watanabe F, Matsushita M, Sakaitani M, Morikami K, Takanashi K, Harada N et al.. (2014) Optimizing the Physicochemical Properties of Raf/MEK Inhibitors by Nitrogen Scanning. ACS Med Chem Lett, 5 (4): 309-14. [PMID:24900832]

3. Bae IH, Son JB, Han SM, Kwak EJ, Kim HS, Song JY, Byun EY, Jun SA, Ahn YG, Suh KH. (2013) THIENO[3,2-d]PYRIMIDINE DERIVATIVES HAVING INHIBITORY ACTIVITY FOR PROTEIN KINASES. Patent number: WO2013100632A1. Assignee: Hanmi Pharm Co. Priority date: 30/12/2011. Publication date: 04/07/2013.

4. Bain J, McLauchlan H, Elliott M, Cohen P. (2003) The specificities of protein kinase inhibitors: an update. Biochem J, 371 (Pt 1): 199-204. [PMID:12534346]

5. Berger DM, Powell DW, Wu B. (2009) 3-quinolinecarbonitrile protein kinase inhibitors. Patent number: US20090062281A1. Assignee: Wyeth LLC. Priority date: 20/02/2004. Publication date: 05/03/2009.

6. Bouhana K, Anderson D, DeWolf W, Brown S, Williams L, Ren L, Moreno D, Wallace R, Fell JB, Hartley D et al.. (2021) Abstract 1473: Nonclinical development of PF-07284890 (ARRY-461), a potent, brain-penetrant, small molecule inhibitor of BRAF V600-mutation-driven tumors in vitro and in vivo. Cancer Research, 81: 1473. DOI: 10.1158/1538-7445.AM2021-1473

7. Chen YK, Kanouni T, Arnold LD, Cox JM, Gardiner E, Grandinetti K, Jiang P, Kaldor SW, Lee C, Li C et al.. (2024) The Discovery of Exarafenib (KIN-2787): Overcoming the Challenges of Pan-RAF Kinase Inhibition. J Med Chem,. DOI: 10.1021/acs.jmedchem.3c01830

8. Chin PC, Liu L, Morrison BE, Siddiq A, Ratan RR, Bottiglieri T, D'Mello SR. (2004) The c-Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK-ERK and Akt-independent mechanism. J Neurochem, 90 (3): 595-608. [PMID:15255937]

9. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1046-51. [PMID:22037378]

10. Fedorov O, Marsden B, Pogacic V, Rellos P, Müller S, Bullock AN, Schwaller J, Sundström M, Knapp S. (2007) A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci USA, 104 (51): 20523-8. [PMID:18077363]

11. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem J, 451 (2): 313-28. [PMID:23398362]

12. Garton AJ, Crew AP, Franklin M, Cooke AR, Wynne GM, Castaldo L, Kahler J, Winski SL, Franks A, Brown EN et al.. (2006) OSI-930: a novel selective inhibitor of Kit and kinase insert domain receptor tyrosine kinases with antitumor activity in mouse xenograft models. Cancer Res, 66 (2): 1015-24. [PMID:16424037]

13. Girotti MR, Lopes F, Preece N, Niculescu-Duvaz D, Zambon A, Davies L, Whittaker S, Saturno G, Viros A, Pedersen M et al.. (2015) Paradox-breaking RAF inhibitors that also target SRC are effective in drug-resistant BRAF mutant melanoma. Cancer Cell, 27 (1): 85-96. [PMID:25500121]

14. Hart AC, Abell L, Guo J, Mertzman ME, Padmanabha R, Macor JE, Chaudhry C, Lu H, O'Malley K, Shaw PJ et al.. (2019) Identification of RIPK3 Type II Inhibitors Using High-Throughput Mechanistic Studies in Hit Triage. ACS Med Chem Lett, Article ASAP. DOI: 10.1021/acsmedchemlett.9b00065

15. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, Ludlam MJ, Stokoe D, Gloor SL, Vigers G et al.. (2010) RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature, 464 (7287): 431-5. [PMID:20130576]

16. Jones DT, Kocialkowski S, Liu L, Pearson DM, Ichimura K, Collins VP. (2009) Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene, 28 (20): 2119-23. [PMID:19363522]

17. Kaldor SW, Kanouni T, Tyhonas J, Murphy EA. (2021) Inhibitors of raf kinases. Patent number: WO2021081375A1. Assignee: Kinnate Biopharma Inc.. Priority date: 24/10/2019. Publication date: 29/04/2021.

18. King AJ, Patrick DR, Batorsky RS, Ho ML, Do HT, Zhang SY, Kumar R, Rusnak DW, Takle AK, Wilson DM et al.. (2006) Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. Cancer Res, 66 (23): 11100-5. [PMID:17145850]

19. Okaniwa M, Hirose M, Arita T, Yabuki M, Nakamura A, Takagi T, Kawamoto T, Uchiyama N, Sumita A, Tsutsumi S et al.. (2013) Discovery of a selective kinase inhibitor (TAK-632) targeting pan-RAF inhibition: design, synthesis, and biological evaluation of C-7-substituted 1,3-benzothiazole derivatives. J Med Chem, 56 (16): 6478-94. [PMID:23906342]

20. Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A et al.. (2007) Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet, 39 (8): 1007-12. [PMID:17603483]

21. Peng SB, Henry JR, Kaufman MD, Lu WP, Smith BD, Vogeti S, Rutkoski TJ, Wise S, Chun L, Zhang Y et al.. (2015) Inhibition of RAF Isoforms and Active Dimers by LY3009120 Leads to Anti-tumor Activities in RAS or BRAF Mutant Cancers. Cancer Cell, 28 (3): 384-98. [PMID:26343583]

22. Ramurthy S, Taft BR, Aversa RJ, Barsanti PA, Burger MT, Lou Y, Nishiguchi GA, Rico A, Setti L, Smith A et al.. (2020) Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-morpholinopyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide, a Selective, Efficacious, and Well-Tolerated RAF Inhibitor Targeting RAS Mutant Cancers: The Path to the Clinic. J Med Chem, 63 (5): 2013-2027. [PMID:31059256]

23. Razzaque MA, Nishizawa T, Komoike Y, Yagi H, Furutani M, Amo R, Kamisago M, Momma K, Katayama H, Nakagawa M et al.. (2007) Germline gain-of-function mutations in RAF1 cause Noonan syndrome. Nat Genet, 39 (8): 1013-7. [PMID:17603482]

24. Rowbottom MW, Faraoni R, Chao Q, Campbell BT, Lai AG, Setti E, Ezawa M, Sprankle KG, Abraham S, Tran L et al.. (2012) Identification of 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea hydrochloride (CEP-32496), a highly potent and orally efficacious inhibitor of V-RAF murine sarcoma viral oncogene homologue B1 (BRAF) V600E. J Med Chem, 55 (3): 1082-105. [PMID:22168626]

25. Wang X, Kim J. (2012) Conformation-specific effects of Raf kinase inhibitors. J Med Chem, 55 (17): 7332-41. [PMID:22808911]

26. Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M et al.. (2004) BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res, 64 (19): 7099-109. [PMID:15466206]

27. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem Biol, 17 (11): 1241-9. [PMID:21095574]

28. Zhang C, Spevak W, Zhang Y, Burton EA, Ma Y, Habets G, Zhang J, Lin J, Ewing T, Matusow B et al.. (2015) RAF inhibitors that evade paradoxical MAPK pathway activation. Nature, 526 (7574): 583-6. [PMID:26466569]

29. Zhou C, Zhang G. (2014) Fused tricyclic urea compounds as raf kinase and/or raf kinase dimer inhibitors. Patent number: WO2014206343A1. Assignee: Beigene, Ltd.. Priority date: 27/06/2014. Publication date: 31/12/2014.

30. Zhu T, Jiao Y, Chen YD, Wang X, Li HF, Zhang LY, Lu T. (2008) Pharmacophore identification of Raf-1 kinase inhibitors. Bioorg Med Chem Lett, 18 (7): 2346-50. [PMID:18346893]

How to cite this page

RAF family: Raf-1 proto-oncogene, serine/threonine kinase. Last modified on 05/03/2024. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2184.