Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTAN5W2)

• DTT Name: Raf messenger RNA (Raf mRNA)
• Synonyms: cRaf (mRNA); Raf-1 (mRNA); RAF proto-oncogene serine/threonine-protein kinase (mRNA); RAF (mRNA)
• Gene Name: RAF1
• DTT Type: Clinical trial target; [1]
• BioChemical Class: mRNA target
• UniProt ID: RAF1_HUMAN
• TTD ID: T52316
• EC Number: EC 2.7.11.1
• Sequence:
  MEHIQGAWKTISNGFGFKDAVFDGSSCISPTIVQQFGYQRRASDDGKLTDPSKTSNTIRV
  FLPNKQRTVVNVRNGMSLHDCLMKALKVRGLQPECCAVFRLLHEHKGKKARLDWNTDAAS
  LIGEELQVDFLDHVPLTTHNFARKTFLKLAFCDICQKFLLNGFRCQTCGYKFHEHCSTKV
  PTMCVDWSNIRQLLLFPNSTIGDSGVPALPSLTMRRMRESVSRMPVSSQHRYSTPHAFTF
  NTSSPSSEGSLSQRQRSTSTPNVHMVSTTLPVDSRMIEDAIRSHSESASPSALSSSPNNL
  SPTGWSQPKTPVPAQRERAPVSGTQEKNKIRPRGQRDSSYYWEIEASEVMLSTRIGSGSF
  GTVYKGKWHGDVAVKILKVVDPTPEQFQAFRNEVAVLRKTRHVNILLFMGYMTKDNLAIV
  TQWCEGSSLYKHLHVQETKFQMFQLIDIARQTAQGMDYLHAKNIIHRDMKSNNIFLHEGL
  TVKIGDFGLATVKSRWSGSQQVEQPTGSVLWMAPEVIRMQDNNPFSFQSDVYSYGIVLYE
  LMTGELPYSHINNRDQIIFMVGRGYASPDLSKLYKNCPKAMKRLVADCVKKVKEERPLFP
  QILSSIELLQHSLPKINRSASEPSLHRAAHTEDINACTLTTSPRLPVF
• Function: RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation. Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation.
• KEGG Pathway:
  MAPK signaling pathway (hsa04010)
  ErbB signaling pathway (hsa04012)
  Ras signaling pathway (hsa04014)
  Rap1 signaling pathway (hsa04015)
  cGMP-PKG signaling pathway (hsa04022)
  cAMP signaling pathway (hsa04024)
  Chemokine signaling pathway (hsa04062)
  FoxO signaling pathway (hsa04068)
  Sphingolipid signaling pathway (hsa04071)
  PI3K-Akt signaling pathway (hsa04151)
  Vascular smooth muscle contraction (hsa04270)
  VEGF signaling pathway (hsa04370)
  Focal adhesion (hsa04510)
  Gap junction (hsa04540)
  Signaling pathways regulating pluripotency of stem cells (hsa04550)
  Natural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor signaling pathway (hsa04660)
  B cell receptor signaling pathway (hsa04662)
  Fc epsilon RI signaling pathway (hsa04664)
  Fc gamma R-mediated phagocytosis (hsa04666)
  Long-term potentiation (hsa04720)
  Neurotrophin signaling pathway (hsa04722)
  Serotonergic synapse (hsa04726)
  Long-term depression (hsa04730)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin signaling pathway (hsa04910)
  GnRH signaling pathway (hsa04912)
  Progesterone-mediated oocyte maturation (hsa04914)
  Estrogen signaling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Prolactin signaling pathway (hsa04917)
  Thyroid hormone signaling pathway (hsa04919)
  Oxytocin signaling pathway (hsa04921)
  Alcoholism (hsa05034)
  Tuberculosis (hsa05152)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Influenza A (hsa05164)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  MicroRNAs in cancer (hsa05206)
  Colorectal cancer (hsa05210)
  Renal cell carcinoma (hsa05211)
  Pancreatic cancer (hsa05212)
  Endometrial cancer (hsa05213)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Melanoma (hsa05218)
  Bladder cancer (hsa05219)
  Chronic myeloid leukemia (hsa05220)
  Acute myeloid leukemia (hsa05221)
  Non-small cell lung cancer (hsa05223)
  Central carbon metabolism in cancer (hsa05230)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  GP1b-IX-V activation signalling (R-HSA-430116)
  CREB phosphorylation through the activation of Ras (R-HSA-442742)
  CD209 (DC-SIGN) signaling (R-HSA-5621575)
  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)
  Stimuli-sensing channels (R-HSA-2672351)

Molecular Interaction Atlas (MIA) of This DTT

6 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]
ICo-007	DM79W8K	Diabetic macular edema	9B71.02	Phase 1	[2]
LErafAON	DMNHPOT	Solid tumour/cancer	2A00-2F9Z	Phase 1	[3]
LXH254	DMQE9PS	Non-small-cell lung cancer	2C25.Y	Phase 1	[4]
RG7304	DMGFAVQ	Solid tumour/cancer	2A00-2F9Z	Phase 1	[5]
SPN-803	DM8O2AQ	Parkinson disease	8A00.0	Phase 1	[1]

21 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
5-(4-hydroxy-2,6-dimethylstyryl)nicotinic acid	DMISOLU	Discovery agent	N.A.	Investigative	[6]
6-Benzylsulfanyl-9H-purine	DMI7FNZ	Discovery agent	N.A.	Investigative	[7]
6-[(E)-2-(4-Fluoro-phenyl)-vinyl]-9H-purine	DMDNG8F	Discovery agent	N.A.	Investigative	[7]
DEBROMOHYMENIALDISINE	DMDLER8	Discovery agent	N.A.	Investigative	[8]
GW-5074	DMIHOYF	Discovery agent	N.A.	Investigative	[9]
ISIS 10707	DMYG5IO	Discovery agent	N.A.	Investigative	[10]
ISIS 11061	DMNKY2R	Discovery agent	N.A.	Investigative	[10]
ISIS 15770	DMJCXHM	Solid tumour/cancer	2A00-2F9Z	Investigative	[11]
ISIS 6717	DM5KGQO	Discovery agent	N.A.	Investigative	[10]
ISIS 6720	DMJS6B0	Discovery agent	N.A.	Investigative	[10]
ISIS 6729	DMWZOQJ	Discovery agent	N.A.	Investigative	[10]
ISIS 7847	DMTN1D7	Discovery agent	N.A.	Investigative	[10]
ISIS 7848	DMOXBDT	Discovery agent	N.A.	Investigative	[10]
ISIS 7849	DMQYB7A	Discovery agent	N.A.	Investigative	[10]
ISIS 7851	DMJKC45	Discovery agent	N.A.	Investigative	[10]
ISIS 7853	DM12E76	Discovery agent	N.A.	Investigative	[10]
ISIS 7855	DMKAQ6U	Discovery agent	N.A.	Investigative	[10]
ISIS 9058	DMD1MEZ	Discovery agent	N.A.	Investigative	[10]
L-790070	DMJKAQR	Autoimmune diabetes	5A10	Investigative	[12]
PLX-ORI3	DMZG1L5	Solid tumour/cancer	2A00-2F9Z	Investigative	[1]
ZM-336372	DMD5JYQ	Discovery agent	N.A.	Investigative	[13]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Melanoma	2C82	Skin	4.47E-01	0.03	0.05
Parkinson's disease	8A00.0	Substantia nigra tissue	2.12E-04	0.49	2.78

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: 2184).
• [2] Clinical pipeline report, company report or official report of ISIS Pharmaceuticals (2009).
• [3] Combination with liposome-entrapped, ends-modified raf antisense oligonucleotide (LErafAON) improves the anti-tumor efficacies of cisplatin, epirubicin, mitoxantrone, docetaxel and gemcitabine. Anticancer Drugs. 2004 Mar;15(3):243-53.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] Clinical pipeline report, company report or official report of Roche.
• [6] Aza-stilbenes as potent and selective c-RAF inhibitors. Bioorg Med Chem Lett. 2006 Oct 15;16(20):5378-83.
• [7] Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors. J Med Chem. 2005 Feb 10;48(3):710-22.
• [8] Aldisine alkaloids from the Philippine sponge Stylissa massa are potent inhibitors of mitogen-activated protein kinase kinase-1 (MEK-1). J Med Chem. 2002 Jan 17;45(2):529-32.
• [9] Discovery and in vitro evaluation of potent TrkA kinase inhibitors: oxindole and aza-oxindoles. Bioorg Med Chem Lett. 2004 Feb 23;14(4):953-7.
• [10] US patent application no. 5,952,229, Antisense oligonucleotide modulation of raf gene expression.
• [11] US patent application no. 7,425,545, Modulation of C-reactive protein expression.
• [12] Design, synthesis, and biological evaluation of novel Tri- and tetrasubstituted imidazoles as highly potent and specific ATP-mimetic inhibitors of ... J Med Chem. 2008 Jul 24;51(14):4122-49.
• [13] The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.