B-Raf proto-oncogene, serine/threonine kinase | RAF family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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B-Raf proto-oncogene, serine/threonine kinase

  Target has curated data in GtoImmuPdb

Target id: 1943

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

Abbreviated Name: B-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 - 766 7q34 BRAF B-Raf proto-oncogene, serine/threonine kinase
Mouse - 804 6 B1 Braf Braf transforming gene
Rat - 804 4q21-q22 Braf B-Raf proto-oncogene, serine/threonine kinase
Previous and Unofficial Names
BRAF1 | Braf2 | v-raf murine sarcoma viral oncogene homolog B1 | v-raf murine sarcoma viral oncogene homolog B | B-Raf 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
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the RBD domain of serine/threonine-protein kinase B-raf from Homo sapiens. Northeast Structural Genomics Consortium Target HR4694F.
PDB Id:  3NY5
Resolution:  1.99Å
Species:  Human
References: 
Image of receptor 3D structure from RCSB PDB
Description:  The complex of wild type B-RAF and BAY439006.
PDB Id:  1UWH
Ligand:  sorafenib
Resolution:  2.95Å
Species:  Human
References:  20
Image of receptor 3D structure from RCSB PDB
Description:  Crystal Structure of Human B-raf bound to a DFG-out Inhibitor TAK-632.
PDB Id:  4KSP
Ligand:  TAK-632
Resolution:  2.93Å
Species:  Human
References:  13
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 8.8 pKd 13
pKd 8.8 (Kd 1.6x10-9 M) [13]
Description: Dissociation constant determined using Surface Plasmon Resonance.
agerafenib Hs Inhibition 7.4 pKd 15
pKd 7.4 (Kd 3.6x10-8 M) [15]
Description: Inhibition of wild type BRAF activity.
PLX-4720 Hs Inhibition 6.5 pKd 5
pKd 6.5 (Kd 3.3x10-7 M) [5]
compound 2 [PMID: 26061392] Hs Inhibition 6.3 pKd 8
pKd 6.3 (Kd 4.44x10-7 M) [8]
CHIR-265 Hs Inhibition 5.9 pKd 5
pKd 5.9 (Kd 1.2x10-6 M) [5]
SB590885 Hs Inhibition 9.8 pKi 10
pKi 9.8 (Ki 1.6x10-10 M) [10]
Description: In a cell-free assay
GDC-0879 Hs Inhibition 9.7 – 9.9 pIC50 5,7
pIC50 9.7 – 9.9 (IC50 1.9x10-10 – 1.3x10-10 M) [5,7]
dabrafenib Hs Inhibition 8.5 pIC50 11
pIC50 8.5 (IC50 3.2x10-9 M) [11]
TAK-632 Hs Inhibition 8.1 pIC50 13
pIC50 8.1 (IC50 8.3x10-9 M) [13]
Description: Biochemical enzyme inhibition assay.
LY3009120 Hs Inhibition 8.0 pIC50 14
pIC50 8.0 (IC50 9.1x10-9 M) [14]
L779450 Hs Inhibition 8.0 pIC50 17
pIC50 8.0 (IC50 1x10-8 M) [17]
PLX8394 Hs Inhibition 7.8 pIC50 25
pIC50 7.8 (IC50 1.4x10-8 M) [25]
sorafenib Hs Inhibition 7.7 pIC50 22
pIC50 7.7 (IC50 2.2x10-8 M) [22]
regorafenib Hs Inhibition 7.6 pIC50 24
pIC50 7.6 (IC50 2.8x10-8 M) [24]
CCT241161 Hs Inhibition 7.5 pIC50 6
pIC50 7.5 (IC50 3x10-8 M) [6]
lifirafenib Hs Inhibition 7.5 pIC50 18
pIC50 7.5 (IC50 3.2x10-8 M) [18]
Description: Inhibition of wild type BRAF kinase domain (aa416-766)
vemurafenib Hs Inhibition 7.0 pIC50 21
pIC50 7.0 (IC50 1x10-7 M) [21]
CCT196969 Hs Inhibition 7.0 pIC50 6
pIC50 7.0 (IC50 1x10-7 M) [6]
PLX-4720 Hs Inhibition 6.8 pIC50 19
pIC50 6.8 (IC50 1.6x10-7 M) [19]
SZM594 Hs Inhibition 6.5 pIC50 3
pIC50 6.5 (IC50 3.22x10-7 M) [3]
Description: Determined in a Latha screen assay.
TAK-580 Hs Inhibition 5.7 pIC50 16
pIC50 5.7 (IC50 1.895x10-6 M) [16]
AZ628 Hs Inhibition - - 9
[9]
Inhibitor Comments
See the ChEMBL link on the Summary tab of the ligand page to view additional kinase targets for regorafenib.
CEP-32496 binds BRAFV600E with a Kd of 14nM, which is lower than its affinity for wild type BRAF [15]. Both CCT196969 and CCT241161 inhibit BRAFV600E with increased potency compared to wild-type- IC50 values vs. V600E are 40nM and 15nM respectively [6].
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: 5,23

Key to terms and symbols Click column headers to sort
Target used in screen: BRAF
Ligand Sp. Type Action Value Parameter
GDC-0879 Hs Inhibitor Inhibition 9.7 pKd
PD-173955 Hs Inhibitor Inhibition 8.2 pKd
tamatinib Hs Inhibitor Inhibition 6.6 pKd
PLX-4720 Hs Inhibitor Inhibition 6.5 pKd
dasatinib Hs Inhibitor Inhibition 6.3 pKd
sorafenib Hs Inhibitor Inhibition 6.3 pKd
motesanib Hs Inhibitor Inhibition 6.2 pKd
SB203580 Hs Inhibitor Inhibition 6.2 pKd
pazopanib Hs Inhibitor Inhibition 6.1 pKd
PP-242 Hs Inhibitor Inhibition 6.1 pKd
Target used in screen: BRAF(V600E)
Ligand Sp. Type Action Value Parameter
GDC-0879 Hs Inhibitor Inhibition 9.7 pKd
PD-173955 Hs Inhibitor Inhibition 8.4 pKd
PLX-4720 Hs Inhibitor Inhibition 7.0 pKd
AST-487 Hs Inhibitor Inhibition 6.9 pKd
sorafenib Hs Inhibitor Inhibition 6.6 pKd
motesanib Hs Inhibitor Inhibition 6.6 pKd
CHIR-265 Hs Inhibitor Inhibition 6.5 pKd
tamatinib Hs Inhibitor Inhibition 6.4 pKd
pazopanib Hs Inhibitor Inhibition 6.4 pKd
SB203580 Hs Inhibitor Inhibition 6.3 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: ...2

Key to terms and symbols Click column headers to sort
Target used in screen: nd/BRAF
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
PKR inhibitor, negative control Hs Inhibitor Inhibition 10.2
nilotinib Hs Inhibitor Inhibition 11.5
sorafenib Hs Inhibitor Inhibition 19.4
dasatinib Hs Inhibitor Inhibition 52.1
TWS119 Hs Inhibitor Inhibition 53.2
JNJ-7706621 Hs Inhibitor Inhibition 55.0
SB202190 Hs Inhibitor Inhibition 60.5
PD 169316 Hs Inhibitor Inhibition 72.0
EGFR/ErbB-2 inhibitor Hs Inhibitor Inhibition 75.6
SB203580 Hs Inhibitor Inhibition 78.8
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
BRAFV600E- immuno-oncology [1]
Immuno Process Associations
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 3 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0043367 CD4-positive, alpha-beta T cell differentiation IEA
GO:0043369 CD4-positive or CD8-positive, alpha-beta T cell lineage commitment IEA
GO:0045580 regulation of T cell differentiation IEA
Immuno Process:  Immune regulation
GO Annotations:  Associated to 2 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0045580 regulation of T cell differentiation IEA
GO:0050852 T cell receptor signaling pathway IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 5 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0002318 myeloid progenitor cell differentiation IEA
GO:0043367 CD4-positive, alpha-beta T cell differentiation IEA
GO:0043369 CD4-positive or CD8-positive, alpha-beta T cell lineage commitment IEA
GO:0045580 regulation of T cell differentiation IEA
GO:0048538 thymus development IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 4 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0043367 CD4-positive, alpha-beta T cell differentiation IEA
GO:0043369 CD4-positive or CD8-positive, alpha-beta T cell lineage commitment IEA
GO:0045580 regulation of T cell differentiation IEA
GO:0050852 T cell receptor signaling pathway IEA
Clinically-Relevant Mutations and Pathophysiology
Disease:  Cardiofaciocutaneous syndrome 1; CFC1
Synonyms: Cardiofaciocutaneous syndrome [Orphanet: ORPHA1340]
OMIM: 115150
Orphanet: ORPHA1340
Disease:  Colorectal cancer
Disease Ontology: DOID:9256
OMIM: 114500
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human V600E The oncogenic V600E non-synonymous mutation is a transforming mutation, and accounts for 80% of BRAF mutations in colorectal cancers. 4
Disease:  Craniopharyngioma
Disease Ontology: DOID:3840
Orphanet: ORPHA54595
Disease:  Hairy cell leukemia
Disease Ontology: DOID:285
Orphanet: ORPHA58017
Disease:  Hashimoto-Pritzker syndrome
Orphanet: ORPHA99872
Disease:  LEOPARD syndrome 3; LPRD3
Synonyms: LEOPARD syndrome [Orphanet: ORPHA500] [Disease Ontology: DOID:14291]
Disease Ontology: DOID:14291
OMIM: 613707
Orphanet: ORPHA500
Disease:  Lung cancer
Disease Ontology: DOID:1324
OMIM: 211980
Role: 
Disease:  Lymphoma, non-hodgkin, familial
Description: A lymphoma that is characterized as any kind of lymphoma except Hodgkin's lymphoma. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and lethargy.
Synonyms: Non-Hodgkin lymphoma [Disease Ontology: DOID:0060060]
Disease Ontology: DOID:0060060
OMIM: 605027
References:  12
Disease:  Noonan syndrome 7; NS7
Synonyms: Noonan syndrome [Orphanet: ORPHA648] [Disease Ontology: DOID:3490]
Disease Ontology: DOID:3490
OMIM: 613706
Orphanet: ORPHA648
Disease:  Pilocytic astrocytoma
Disease Ontology: DOID:4851
Orphanet: ORPHA251612

References

Show »

1. Adams JL, Smothers J, Srinivasan R, Hoos A. (2015) Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov, 14 (9): 603-22. [PMID:26228631]

2. 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]

3. Chen X, Zhuang C, Ren Y, Zhang H, Qin X, Hu L, Fu J, Miao Z, Chai Y, Liu ZG et al.. (2019) Identification of the Raf kinase inhibitor TAK-632 and its analogues as potent inhibitors of necroptosis by targeting RIPK1 and RIPK3. Br. J. Pharmacol., 176 (12): 2095-2108. [PMID:30825190]

4. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W et al.. (2002) Mutations of the BRAF gene in human cancer. Nature, 417 (6892): 949-54. [PMID:12068308]

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. 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]

7. Hansen JD, Grina J, Newhouse B, Welch M, Topalov G, Littman N, Callejo M, Gloor S, Martinson M, Laird E et al.. (2008) Potent and selective pyrazole-based inhibitors of B-Raf kinase. Bioorg. Med. Chem. Lett., 18 (16): 4692-5. [PMID:18676143]

8. Horbert R, Pinchuk B, Davies P, Alessi D, Peifer C. (2015) Photoactivatable Prodrugs of Antimelanoma Agent Vemurafenib. ACS Chem. Biol., 10 (9): 2099-107. [PMID:26061392]

9. Khazak V, Astsaturov I, Serebriiskii IG, Golemis EA. (2007) Selective Raf inhibition in cancer therapy. Expert Opin. Ther. Targets, 11 (12): 1587-609. [PMID:18020980]

10. 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]

11. Laquerre S, Arnone M, Moss K, Yang J, Fisher K, Kane-Carson LS, Smitheman K, Ward J, Heidrich B, Rheault T et al. (2009) Abstract B88: A selective Raf kinase inhibitor induces cell death and tumor regression of human cancer cell lines encoding B-RafV600E mutation. Molecular Cancer Therapeutics, 8 (12) Meeting Abstract.

12. Lee JW, Yoo NJ, Soung YH, Kim HS, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ et al.. (2003) BRAF mutations in non-Hodgkin's lymphoma. Br. J. Cancer, 89 (10): 1958-60. [PMID:14612909]

13. 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]

14. 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]

15. 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]

16. Sun Y, Alberta JA, Pilarz C, Calligaris D, Chadwick EJ, Ramkissoon SH, Ramkissoon LA, Garcia VM, Mazzola E, Goumnerova L et al.. (2017) A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas. Neuro-oncology, 19 (6): 774-785. [PMID:28082416]

17. Takle AK, Brown MJ, Davies S, Dean DK, Francis G, Gaiba A, Hird AW, King FD, Lovell PJ, Naylor A et al.. (2006) The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorg. Med. Chem. Lett., 16 (2): 378-81. [PMID:16260133]

18. Tang Z, Yuan X, Du R, Cheung SH, Zhang G, Wei J, Zhao Y, Feng Y, Peng H, Zhang Y et al.. (2015) BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers. Mol. Cancer Ther., 14 (10): 2187-97. [PMID:26208524]

19. Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK et al.. (2008) Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc. Natl. Acad. Sci. U.S.A., 105 (8): 3041-6. [PMID:18287029]

20. Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D et al.. (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell, 116 (6): 855-67. [PMID:15035987]

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

22. 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]

23. 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]

24. Zambon A, Niculescu-Duvaz I, Niculescu-Duvaz D, Marais R, Springer CJ. (2012) Small molecule inhibitors of BRAF in clinical trials. Bioorg. Med. Chem. Lett., 22 (2): 789-92. [PMID:22222036]

25. 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]

How to cite this page

RAF family: B-Raf proto-oncogene, serine/threonine kinase. Last modified on 16/05/2019. Accessed on 17/10/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=1943.