Raf-1 proto-oncogene, serine/threonine kinase | RAF family | IUPHAR/BPS Guide to PHARMACOLOGY

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Raf-1 proto-oncogene, serine/threonine kinase

Target not currently curated in GtoImmuPdb

Target id: 2184

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

Abbreviated Name: c-Raf

Family: RAF family

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 648 3p25 RAF1 Raf-1 proto-oncogene, serine/threonine kinase
Mouse - 648 6 3 Raf1 v-raf-leukemia viral oncogene 1
Rat - 648 4 q42 Raf1 Raf-1 proto-oncogene
Previous and Unofficial Names
RAF proto-oncogene serine/threonine-protein kinase | Raf-1 proto-oncogene
Database Links
BRENDA
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
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:  11
Enzyme Reaction
EC Number: 2.7.11.1

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
TAK-632 Hs Inhibition 9.3 pKd 14
pKd 9.3 (Kd 5.2x10-10 M) [14]
Description: Dissociation constant determined by Surface Plasmon Resonance.
agerafenib Hs Inhibition 7.4 pKd 18
pKd 7.4 (Kd 3.9x10-8 M) [18]
L779450 Hs Inhibition 8.9 pIC50 23
pIC50 8.9 (IC50 1.4x10-9 M) [23]
TAK-632 Hs Inhibition 8.9 pIC50 14
pIC50 8.9 (IC50 1.4x10-9 M) [14]
Description: Biochemical enzyme inhibition assay.
SB590885 Hs Inhibition 8.8 pIC50 13
pIC50 8.8 (IC50 1.72x10-9 M) [13]
Description: In a cell-free assay
sorafenib Hs Inhibition 8.2 pIC50 20
pIC50 8.2 (IC50 6x10-9 M) [20]
CCT241161 Hs Inhibition 8.2 pIC50 9
pIC50 8.2 (IC50 6x10-9 M) [9]
GW5074 Hs Inhibition 8.1 pIC50 4
pIC50 8.1 (IC50 9x10-9 M) [4]
CCT196969 Hs Inhibition 8.0 pIC50 9
pIC50 8.0 (IC50 1x10-8 M) [9]
RIPK3 inhibitor 18 Hs Inhibition 8.0 pIC50 10
pIC50 8.0 (IC50 1.1x10-8 M) [10]
LY3009120 Hs Inhibition 7.8 pIC50 16
pIC50 7.8 (IC50 1.5x10-8 M) [16]
PLX8394 Hs Inhibition 7.6 pIC50 22
pIC50 7.6 (IC50 2.3x10-8 M) [22]
OSI-930 Hs Inhibition 7.4 pIC50 8
pIC50 7.4 (IC50 4.1x10-8 M) [8]
ZM336372 Hs Inhibition 7.2 – 7.5 pIC50 2,6
pIC50 7.2 – 7.5 (IC50 7x10-8 – 3.1x10-8 M) [2,6]
balamapimod Hs Inhibition 6.9 pIC50 3
pIC50 6.9 (IC50 1.14x10-7 M) [3]
Description: Measuring c-Raf mediated activation of MEK and phosphorylation of MEK substrate.
vemurafenib Hs Inhibition 6.4 – 7.3 pIC50 16,19
pIC50 6.4 – 7.3 (IC50 4.14x10-7 – 4.8x10-8 M) [16,19]
DiscoveRx KINOMEscan® screen
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: 5,21

Key to terms and symbols Click column headers to sort
Target used in screen: RAF1
Ligand Sp. Type Action Value Parameter
GDC-0879 Hs Inhibitor Inhibition 8.2 pKd
PD-173955 Hs Inhibitor Inhibition 7.6 pKd
PLX-4720 Hs Inhibitor Inhibition 6.8 pKd
sorafenib Hs Inhibitor Inhibition 6.6 pKd
CHIR-265 Hs Inhibitor Inhibition 6.4 pKd
dasatinib Hs Inhibitor Inhibition 6.2 pKd
tamatinib Hs Inhibitor Inhibition 6.1 pKd
motesanib Hs Inhibitor Inhibition 6.1 pKd
pazopanib Hs Inhibitor Inhibition 6.1 pKd
AST-487 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
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: 1,7

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 Hs Inhibitor Inhibition 1.4
PKR inhibitor, negative control Hs Inhibitor Inhibition 6.9 2.0 -2.0
pazopanib Hs Inhibitor Inhibition 9.4
SB202190 Hs Inhibitor Inhibition 25.8 14.0 1.0
dasatinib Hs Inhibitor Inhibition 39.7
SB203580 Hs Inhibitor Inhibition 41.1 17.0 3.0
PD 169316 Hs Inhibitor Inhibition 43.9 20.0 13.0
imatinib Hs Inhibitor Inhibition 47.9
EGFR/ErbB-2 inhibitor Hs Inhibitor Inhibition 61.0 86.0 96.0
p38 MAP kinase inhibitor Hs Inhibitor Inhibition 61.4 33.0 6.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Clinically-Relevant Mutations and Pathophysiology
Disease:  LEOPARD syndrome 2; LPRD2
Synonyms: LEOPARD syndrome [Orphanet: ORPHA500] [Disease Ontology: DOID:14291]
Disease Ontology: DOID:14291
OMIM: 611554
Orphanet: ORPHA500
References:  15
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human S257L 770C>T 15
Missense Human L613V 1837C>G 15
Disease:  Noonan syndrome 5; NS5
Synonyms: Noonan syndrome [Orphanet: ORPHA648] [Disease Ontology: DOID:3490]
Disease Ontology: DOID:3490
OMIM: 611553
Orphanet: ORPHA648
References:  15,17
Disease:  Pilocytic astrocytoma
Disease Ontology: DOID:4851
Orphanet: ORPHA251612
References:  12

References

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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. 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]

3. 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.

4. 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]

5. 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]

6. 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. U.S.A., 104 (51): 20523-8. [PMID:18077363]

7. 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]

8. 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]

9. 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]

10. 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 Medicinal Chemistry Letters, Article ASAP. DOI: 10.1021/acsmedchemlett.9b00065

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

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

20. 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]

21. 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]

22. 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]

23. 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 17/05/2019. Accessed on 23/08/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2184.