Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT0EOB8)

• DTT Name: B-Raf messenger RNA (BRAF mRNA)
• Synonyms: V-Raf murine sarcoma viral oncogene homolog B1 (mRNA); Serine/threonine-protein kinase B-raf (mRNA); RAFB1 (mRNA); Proto-oncogene B-Raf (mRNA); P94 (mRNA); BRAF1 (mRNA); BRAF(V599E) (mRNA); BRAF serine/threonine kinase (mRNA); B-raf protein (mRNA); B-Raf (mRNA)
• Gene Name: BRAF
• DTT Type: Clinical trial target; [1]
• Related Disease:
  Melanoma [ICD-11: 2C30]
  Parkinsonism [ICD-11: 8A00]
  Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• BioChemical Class: mRNA target
• UniProt ID: BRAF_HUMAN
• TTD ID: T90648
• 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

4 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MLN2480	DMBR8NF	Solid tumour/cancer	2A00-2F9Z	Phase 2	[1]
PLX-4720	DMBK9AM	Cutaneous melanoma	2C30	Phase 1	[2]
RG7304	DMGFAVQ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[3]
SPN-803	DM8O2AQ	Parkinson disease	8A00.0	Phase 1	[1]

13 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
2-(Benzylamino)-6-(3-acetamidophenyl)pyrazine	DM4X6I9	Discovery agent	N.A.	Investigative	[4]
2-(Phenylamino)-6-(3-acetamidophenyl)pyrazine	DMPUARE	Discovery agent	N.A.	Investigative	[4]
ISIS 13727	DMCDW4H	Discovery agent	N.A.	Investigative	[5]
ISIS 13730	DMRJBH4	Discovery agent	N.A.	Investigative	[5]
ISIS 13740	DM5Q12D	Discovery agent	N.A.	Investigative	[5]
ISIS 13741	DMC7Q38	Discovery agent	N.A.	Investigative	[5]
ISIS 13743	DMO6R1I	Discovery agent	N.A.	Investigative	[5]
ISIS 14144	DMWIKD5	Discovery agent	N.A.	Investigative	[5]
L-779450	DM51B74	Discovery agent	N.A.	Investigative	[6]
PLX-ORI3	DMZG1L5	Solid tumour/cancer	2A00-2F9Z	Investigative	[1]
PMID26061392C2	DMHZOIU	Discovery agent	N.A.	Investigative	[7]
Pyrazolo[1,5-a]pyrimidine-3-carboxylate	DM69LKB	Discovery agent	N.A.	Investigative	[8]
ZM-336372	DMD5JYQ	Discovery agent	N.A.	Investigative	[9]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Parkinson's disease	8A00.0	Substantia nigra tissue	1.56E-01	-0.23	-0.43

References

• [1] 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. (Target id: 1943).
• [2] Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011 Oct 30;29(11):1046-51.
• [3] Clinical pipeline report, company report or official report of Roche.
• [4] Novel inhibitors of B-RAF based on a disubstituted pyrazine scaffold. Generation of a nanomolar lead. J Med Chem. 2006 Jan 12;49(1):407-16.
• [5] US patent application no. 5,981,731, Antisense oligonucleotide modulation of B-raf gene expression.
• [6] The identification of potent and selective imidazole-based inhibitors of B-Raf kinase. Bioorg Med Chem Lett. 2006 Jan 15;16(2):378-81.
• [7] Photoactivatable Prodrugs of Antimelanoma Agent Vemurafenib. ACS Chem Biol. 2015 Sep 18;10(9):2099-107.
• [8] Identification of pyrazolo[1,5-a]pyrimidine-3-carboxylates as B-Raf kinase inhibitors. Bioorg Med Chem Lett. 2009 May 15;19(10):2735-8.
• [9] The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.