Target Information

Target General Information

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Target ID

T52316 (Former ID: TTDR00129)

Target Name

Raf messenger RNA (Raf mRNA)

Synonyms

cRaf (mRNA); Raf-1 (mRNA); RAF proto-oncogene serine/threonine-protein kinase (mRNA); RAF (mRNA)

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Gene Name

RAF1

Target Type

Clinical trial target

[1]

Disease

[+] 5 Target-related Diseases

Lung cancer [ICD-11: 2C25]

Melanoma [ICD-11: 2C30]

Parkinsonism [ICD-11: 8A00]

Retinopathy [ICD-11: 9B71]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

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.

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BioChemical Class

mRNA target

UniProt ID

RAF1_HUMAN

EC Number

EC 2.7.11.1

Sequence

MEHIQGAWKTISNGFGFKDAVFDGSSCISPTIVQQFGYQRRASDDGKLTDPSKTSNTIRV
FLPNKQRTVVNVRNGMSLHDCLMKALKVRGLQPECCAVFRLLHEHKGKKARLDWNTDAAS
LIGEELQVDFLDHVPLTTHNFARKTFLKLAFCDICQKFLLNGFRCQTCGYKFHEHCSTKV
PTMCVDWSNIRQLLLFPNSTIGDSGVPALPSLTMRRMRESVSRMPVSSQHRYSTPHAFTF
NTSSPSSEGSLSQRQRSTSTPNVHMVSTTLPVDSRMIEDAIRSHSESASPSALSSSPNNL
SPTGWSQPKTPVPAQRERAPVSGTQEKNKIRPRGQRDSSYYWEIEASEVMLSTRIGSGSF
GTVYKGKWHGDVAVKILKVVDPTPEQFQAFRNEVAVLRKTRHVNILLFMGYMTKDNLAIV
TQWCEGSSLYKHLHVQETKFQMFQLIDIARQTAQGMDYLHAKNIIHRDMKSNNIFLHEGL
TVKIGDFGLATVKSRWSGSQQVEQPTGSVLWMAPEVIRMQDNNPFSFQSDVYSYGIVLYE
LMTGELPYSHINNRDQIIFMVGRGYASPDLSKLYKNCPKAMKRLVADCVKKVKEERPLFP
QILSSIELLQHSLPKINRSASEPSLHRAAHTEDINACTLTTSPRLPVF

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Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 6 Clinical Trial Drugs

MLN2480

Drug Info

Phase 2

Solid tumour/cancer

[2]

ICo-007

Drug Info

Phase 1

Diabetic retinopathy

[3]

LErafAON

Drug Info

Phase 1

Solid tumour/cancer

[4], [5]

LXH254

Drug Info

Phase 1

Non-small-cell lung cancer

[2]

RG7304

Drug Info

Phase 1

Solid tumour/cancer

[6]

SPN-803

Drug Info

Phase 1

Parkinson disease

[7]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 11 Inhibitor drugs

MLN2480

Drug Info

[1], [8]

LXH254

Drug Info

[2]

SPN-803

Drug Info

[1]

5-(4-hydroxy-2,6-dimethylstyryl)nicotinic acid

Drug Info

[13]

6-Benzylsulfanyl-9H-purine

Drug Info

[14]

6-[(E)-2-(4-Fluoro-phenyl)-vinyl]-9H-purine

Drug Info

[14]

DEBROMOHYMENIALDISINE

Drug Info

[15]

GW-5074

Drug Info

[16]

L-790070

Drug Info

[19]

PLX-ORI3

Drug Info

[1]

ZM-336372

Drug Info

[20]

Modulator

[+] 1 Modulator drugs

RG7304

Drug Info

[12]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Affiliated Biological Pathways		Top
BioCyc	[+] 1 BioCyc Pathways	+
1	MAP kinase cascade
KEGG Pathway	[+] 54 KEGG Pathways	+
1	MAPK signaling pathway
2	ErbB signaling pathway
3	Ras signaling pathway
4	Rap1 signaling pathway
5	cGMP-PKG signaling pathway
6	cAMP signaling pathway
7	Chemokine signaling pathway
8	FoxO signaling pathway
9	Sphingolipid signaling pathway
10	PI3K-Akt signaling pathway
11	Vascular smooth muscle contraction
12	VEGF signaling pathway
13	Focal adhesion
14	Gap junction
15	Signaling pathways regulating pluripotency of stem cells
16	Natural killer cell mediated cytotoxicity
17	T cell receptor signaling pathway
18	B cell receptor signaling pathway
19	Fc epsilon RI signaling pathway
20	Fc gamma R-mediated phagocytosis
21	Long-term potentiation
22	Neurotrophin signaling pathway
23	Serotonergic synapse
24	Long-term depression
25	Regulation of actin cytoskeleton
26	Insulin signaling pathway
27	GnRH signaling pathway
28	Progesterone-mediated oocyte maturation
29	Estrogen signaling pathway
30	Melanogenesis
31	Prolactin signaling pathway
32	Thyroid hormone signaling pathway
33	Oxytocin signaling pathway
34	Alcoholism
35	Tuberculosis
36	Hepatitis C
37	Hepatitis B
38	Influenza A
39	Pathways in cancer
40	Proteoglycans in cancer
41	MicroRNAs in cancer
42	Colorectal cancer
43	Renal cell carcinoma
44	Pancreatic cancer
45	Endometrial cancer
46	Glioma
47	Prostate cancer
48	Melanoma
49	Bladder cancer
50	Chronic myeloid leukemia
51	Acute myeloid leukemia
52	Non-small cell lung cancer
53	Central carbon metabolism in cancer
54	Choline metabolism in cancer
NetPath Pathway	[+] 3 NetPath Pathways	+
1	IL5 Signaling Pathway
2	IL2 Signaling Pathway
3	EGFR1 Signaling Pathway
Panther Pathway	[+] 15 Panther Pathways	+
1	Angiogenesis
2	B cell activation
3	EGF receptor signaling pathway
4	Endothelin signaling pathway
5	FGF signaling pathway
6	Inflammation mediated by chemokine and cytokine signaling pathway
7	Insulin/IGF pathway-mitogen activated protein kinase kinase/MAP kinase cascade
8	Integrin signalling pathway
9	Interleukin signaling pathway
10	PDGF signaling pathway
11	T cell activation
12	VEGF signaling pathway
13	Ras Pathway
14	Angiotensin II-stimulated signaling through G proteins and beta-arrestin
15	CCKR signaling map ST
Pathwhiz Pathway	[+] 2 Pathwhiz Pathways	+
1	Fc Epsilon Receptor I Signaling in Mast Cells
2	Insulin Signalling
PID Pathway	[+] 27 PID Pathways	+
1	Fc-epsilon receptor I signaling in mast cells
2	Endothelins
3	BCR signaling pathway
4	GMCSF-mediated signaling events
5	Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met)
6	CDC42 signaling events
7	SHP2 signaling
8	mTOR signaling pathway
9	IL2-mediated signaling events
10	IGF1 pathway
11	Ras signaling in the CD4+ TCR pathway
12	Ceramide signaling pathway
13	ErbB1 downstream signaling
14	ErbB2/ErbB3 signaling events
15	PDGFR-beta signaling pathway
16	p38 signaling mediated by MAPKAP kinases
17	Nongenotropic Androgen signaling
18	Internalization of ErbB1
19	CXCR3-mediated signaling events
20	Signaling events mediated by Stem cell factor receptor (c-Kit)
21	Signaling events mediated by VEGFR1 and VEGFR2
22	Class I PI3K signaling events mediated by Akt
23	Trk receptor signaling mediated by the MAPK pathway
24	Downstream signaling in na&#xef
25
26	Regulation of retinoblastoma protein
27	Signaling events mediated by focal adhesion kinase
Reactome	[+] 8 Reactome Pathways	+
1	Stimuli-sensing channels
2	GP1b-IX-V activation signalling
3	CREB phosphorylation through the activation of Ras
4	CD209 (DC-SIGN) signaling
5	RAF activation
6	MAP2K and MAPK activation
7	Negative feedback regulation of MAPK pathway
8	Negative regulation of MAPK pathway
WikiPathways	[+] 41 WikiPathways	+
1	Serotonin Receptor 2 and ELK-SRF/GATA4 signaling
2	TCR Signaling Pathway
3	Senescence and Autophagy in Cancer
4	EPO Receptor Signaling
5	Regulation of Actin Cytoskeleton
6	IL-2 Signaling Pathway
7	Insulin Signaling
8	EGF/EGFR Signaling Pathway
9	MAPK Cascade
10	MAPK Signaling Pathway
11	TGF beta Signaling Pathway
12	Signaling of Hepatocyte Growth Factor Receptor
13	Kit receptor signaling pathway
14	Extracellular vesicle-mediated signaling in recipient cells
15	IL-3 Signaling Pathway
16	Cardiac Hypertrophic Response
17	Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell
18	RAF/MAP kinase cascade
19	Iron uptake and transport
20	Nanoparticle-mediated activation of receptor signaling
21	PDGF Pathway
22	Retinoblastoma (RB) in Cancer
23	BDNF signaling pathway
24	Integrated Pancreatic Cancer Pathway
25	Oncostatin M Signaling Pathway
26	Corticotropin-releasing hormone
27	Interleukin-11 Signaling Pathway
28	AGE/RAGE pathway
29	TNF alpha Signaling Pathway
30	B Cell Receptor Signaling Pathway
31	Prostate Cancer
32	Signaling Pathways in Glioblastoma
33	Endothelin Pathways
34	TWEAK Signaling Pathway
35	FSH signaling pathway
36	Leptin signaling pathway
37	Rap1 signalling
38	Integrin-mediated Cell Adhesion
39	GP1b-IX-V activation signalling
40	MicroRNAs in cardiomyocyte hypertrophy
41	IL-5 Signaling Pathway

References

Top

REF 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).

REF 2

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 3

Clinical pipeline report, company report or official report of ISIS Pharmaceuticals (2011).

REF 4

ClinicalTrials.gov (NCT00100672) Study to Determine the Maximum Tolerated Dose of LErafAON in Patients With Advanced Cancer. U.S. National Institutes of Health.

REF 5

Delivery of a liposomal c-raf-1 antisense oligonucleotide by weekly bolus dosing in patients with advanced solid tumors: a phase I study. Clin Cancer Res. 2004 Nov 1;10(21):7244-51.

REF 6

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029782)

REF 7

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029757)

REF 8

National Cancer Institute Drug Dictionary (drug id 710688).

REF 9

Clinical pipeline report, company report or official report of ISIS Pharmaceuticals (2009).

REF 10

Design and development of antisense drugs. Expert Opin. Drug Discov. 2008 3(10):1189-1207.

REF 11

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.

REF 12

Clinical pipeline report, company report or official report of Roche.

REF 13

Aza-stilbenes as potent and selective c-RAF inhibitors. Bioorg Med Chem Lett. 2006 Oct 15;16(20):5378-83.

REF 14

Synthesis and biological testing of purine derivatives as potential ATP-competitive kinase inhibitors. J Med Chem. 2005 Feb 10;48(3):710-22.

REF 15

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.

REF 16

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.

REF 17

US patent application no. 5,952,229, Antisense oligonucleotide modulation of raf gene expression.

REF 18

US patent application no. 7,425,545, Modulation of C-reactive protein expression.

REF 19

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.

REF 20

The selectivity of protein kinase inhibitors: a further update. Biochem J. 2007 Dec 15;408(3):297-315.

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