Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTWCGQT)

• DTT Name: Serine/threonine-protein kinase B-raf (BRAF)
• Synonyms: V-Raf murine sarcoma viral oncogene homolog B1; RAFB1; Proto-oncogene B-Raf; P94; BRAF1; BRAF(V599E); BRAF serine/threonine kinase; B-raf protein; B-Raf
• Gene Name: BRAF
• DTT Type: Successful target; [1]
• Related Disease: Melanoma [ICD-11: 2C30]
• BioChemical Class: Kinase
• UniProt ID: BRAF_HUMAN
• TTD ID: T99089
• EC Number: EC 2.7.11.1
• Sequence:
  MAALSGGGGGGAEPGQALFNGDMEPEAGAGAGAAASSAADPAIPEEVWNIKQMIKLTQEH
  IEALLDKFGGEHNPPSIYLEAYEEYTSKLDALQQREQQLLESLGNGTDFSVSSSASMDTV
  TSSSSSSLSVLPSSLSVFQNPTDVARSNPKSPQKPIVRVFLPNKQRTVVPARCGVTVRDS
  LKKALMMRGLIPECCAVYRIQDGEKKPIGWDTDISWLTGEELHVEVLENVPLTTHNFVRK
  TFFTLAFCDFCRKLLFQGFRCQTCGYKFHQRCSTEVPLMCVNYDQLDLLFVSKFFEHHPI
  PQEEASLAETALTSGSSPSAPASDSIGPQILTSPSPSKSIPIPQPFRPADEDHRNQFGQR
  DRSSSAPNVHINTIEPVNIDDLIRDQGFRGDGGSTTGLSATPPASLPGSLTNVKALQKSP
  GPQRERKSSSSSEDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGSGSFGTVYKGKWHGDV
  AVKMLNVTAPTPQQLQAFKNEVGVLRKTRHVNILLFMGYSTKPQLAIVTQWCEGSSLYHH
  LHIIETKFEMIKLIDIARQTAQGMDYLHAKSIIHRDLKSNNIFLHEDLTVKIGDFGLATV
  KSRWSGSHQFEQLSGSILWMAPEVIRMQDKNPYSFQSDVYAFGIVLYELMTGQLPYSNIN
  NRDQIIFMVGRGYLSPDLSKVRSNCPKAMKRLMAECLKKKRDERPLFPQILASIELLARS
  LPKIHRSASEPSLNRAGFQTEDFSLYACASPKTPIQAGGYGAFPVH
• Function: May play a role in the postsynaptic responses of hippocampal neuron. Phosphorylates MAP2K1, and thereby contributes to the MAP kinase signal transduction pathway. Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  ErbB signaling pathway (hsa04012)
  Rap1 signaling pathway (hsa04015)
  cAMP signaling pathway (hsa04024)
  Chemokine signaling pathway (hsa04062)
  FoxO signaling pathway (hsa04068)
  mTOR signaling pathway (hsa04150)
  Vascular smooth muscle contraction (hsa04270)
  Focal adhesion (hsa04510)
  Natural killer cell mediated cytotoxicity (hsa04650)
  Long-term potentiation (hsa04720)
  Neurotrophin signaling pathway (hsa04722)
  Serotonergic synapse (hsa04726)
  Long-term depression (hsa04730)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin signaling pathway (hsa04910)
  Progesterone-mediated oocyte maturation (hsa04914)
  Alcoholism (hsa05034)
  Hepatitis C (hsa05160)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Colorectal cancer (hsa05210)
  Renal cell carcinoma (hsa05211)
  Pancreatic cancer (hsa05212)
  Endometrial cancer (hsa05213)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Thyroid cancer (hsa05216)
  Melanoma (hsa05218)
  Bladder cancer (hsa05219)
  Chronic myeloid leukemia (hsa05220)
  Acute myeloid leukemia (hsa05221)
  Non-small cell lung cancer (hsa05223)
• Reactome Pathway:
  Frs2-mediated activation (R-HSA-170968)
  ARMS-mediated activation (R-HSA-170984)
  CREB phosphorylation through the activation of Ras (R-HSA-442742)
  RAF activation (R-HSA-5673000)
  MAP2K and MAPK activation (R-HSA-5674135)
  Negative feedback regulation of MAPK pathway (R-HSA-5674499)
  Negative regulation of MAPK pathway (R-HSA-5675221)
  Spry regulation of FGF signaling (R-HSA-1295596)

Molecular Interaction Atlas (MIA) of This DTT

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Dabrafenib	DMX6OE3	Melanoma	2C30	Approved	[1], [2]
LGX818	DMNQXV8	Melanoma	2C30	Approved	[3]
Vemurafenib	DM62UG5	Melanoma	2C30	Approved	[4]

8 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PLX8394	DMRTD7I	Solid tumour/cancer	2A00-2F9Z	Phase 2	[5]
BGB-283	DMVYTG7	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[6]
CEP-32496	DMAO04B	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[7]
ABM-1310	DMS1HR3	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
ARQ 736	DMP9ZT1	Solid tumour/cancer	2A00-2F9Z	Phase 1	[9]
ASN003	DMJCX6D	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
BMS-908662	DM3K8VM	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
RO-5212054	DML4C3Q	Solid tumour/cancer	2A00-2F9Z	Phase 1	[12]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
RG-7256	DM0LXBW	Melanoma	2C30	Discontinued in Phase 1	[13]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AR-00341677	DMK2XB7	Solid tumour/cancer	2A00-2F9Z	Investigative	[14]
AZ-628	DMEWQHP	Solid tumour/cancer	2A00-2F9Z	Investigative	[15]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Thyroid cancer	2C82	Thyroid	3.00E-01	0.1	0.2
Melanoma	2C82	Skin	1.19E-02	0.45	0.73
Myelodysplastic syndrome	2C82	Bone marrow	7.80E-01	0.05	0.08
Breast cancer	2C82	Breast tissue	4.81E-15	0.29	0.47
Acute myelocytic leukaemia	2C82	Bone marrow	5.37E-03	-0.23	-0.36
Head and neck cancer	2C82	Head and neck tissue	5.14E-02	-0.13	-0.27

References

• [1] Clinical pipeline report, company report or official report of GlaxoSmithKline (2011).
• [2] Caspase inhibitors: a review of recently patented compounds (2013-2015).Expert Opin Ther Pat. 2018 Jan;28(1):47-59.
• [3] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [4] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [5] Identification of PLX4032-resistance mechanisms and implications for novel RAF inhibitors. Pigment Cell Melanoma Res. 2014 Mar;27(2):253-62.
• [6] BGB-283, a Novel RAF Kinase and EGFR Inhibitor, Displays Potent Antitumor Activity in BRAF-Mutated Colorectal Cancers. Mol Cancer Ther. 2015 Oct;14(10):2187-97.
• [7] Clinical pipeline report, company report or official report of Ambit Biosciences.
• [8] Clinical pipeline report, company report or official report of ABM Therapeutics.
• [9] National Cancer Institute Drug Dictionary (drug id 688029).
• [10] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [11] Clinical pipeline report, company report or official report of Exelixis (2011).
• [12] National Cancer Institute Drug Dictionary (drug id 680347).
• [13] First-in-Man Dose-Escalation Study of the Selective BRAF Inhibitor RG7256 in Patients with BRAF V600-Mutated Advanced Solid Tumors. Target Oncol. 2016 Apr;11(2):149-56.
• [14] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 5681).
• [15] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8475).