Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT51LSFO)

DOT Name	RAF proto-oncogene serine/threonine-protein kinase (RAF1)
Synonyms	EC 2.7.11.1; Proto-oncogene c-RAF; cRaf; Raf-1
Gene Name	RAF1
Related Disease	Noonan syndrome ( ) Noonan syndrome 5 ( ) Dilated cardiomyopathy 1NN ( ) LEOPARD syndrome 2 ( ) Noonan syndrome with multiple lentigines ( ) Obsolete familial isolated dilated cardiomyopathy ( ) Cardiofaciocutaneous syndrome ( ) Costello syndrome ( )
UniProt ID	RAF1_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	1C1Y ; 1FAQ ; 1FAR ; 1GUA ; 1RFA ; 3CU8 ; 3IQJ ; 3IQU ; 3IQV ; 3KUC ; 3KUD ; 3NKX ; 3O8I ; 3OMV ; 4FJ3 ; 4G0N ; 4G3X ; 4IEA ; 4IHL ; 6NTC ; 6NTD ; 6PTS ; 6PTW ; 6VJJ ; 6XGU ; 6XGV ; 6XHA ; 6XHB ; 6XI7 ; 7JHP ; 7Z37 ; 7Z38 ; 8A68 ; 8A6F ; 8A6H ; 8ATR ; 8ATS ; 8AV0 ; 8EPW ; 8GAE ; 8GFT
EC Number	2.7.11.1
Pfam ID	PF00130 ; PF00069 ; PF02196
Sequence	MEHIQGAWKTISNGFGFKDAVFDGSSCISPTIVQQFGYQRRASDDGKLTDPSKTSNTIRV FLPNKQRTVVNVRNGMSLHDCLMKALKVRGLQPECCAVFRLLHEHKGKKARLDWNTDAAS LIGEELQVDFLDHVPLTTHNFARKTFLKLAFCDICQKFLLNGFRCQTCGYKFHEHCSTKV PTMCVDWSNIRQLLLFPNSTIGDSGVPALPSLTMRRMRESVSRMPVSSQHRYSTPHAFTF NTSSPSSEGSLSQRQRSTSTPNVHMVSTTLPVDSRMIEDAIRSHSESASPSALSSSPNNL SPTGWSQPKTPVPAQRERAPVSGTQEKNKIRPRGQRDSSYYWEIEASEVMLSTRIGSGSF GTVYKGKWHGDVAVKILKVVDPTPEQFQAFRNEVAVLRKTRHVNILLFMGYMTKDNLAIV TQWCEGSSLYKHLHVQETKFQMFQLIDIARQTAQGMDYLHAKNIIHRDMKSNNIFLHEGL TVKIGDFGLATVKSRWSGSQQVEQPTGSVLWMAPEVIRMQDNNPFSFQSDVYSYGIVLYE LMTGELPYSHINNRDQIIFMVGRGYASPDLSKLYKNCPKAMKRLVADCVKKVKEERPLFP QILSSIELLQHSLPKINRSASEPSLHRAAHTEDINACTLTTSPRLPVF
Function	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. 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.
Tissue Specificity	In skeletal muscle, isoform 1 is more abundant than isoform 2.
KEGG Pathway	EGFR tyrosine ki.se inhibitor resistance (hsa01521 ) Endocrine resistance (hsa01522 ) MAPK sig.ling pathway (hsa04010 ) ErbB sig.ling pathway (hsa04012 ) Ras sig.ling pathway (hsa04014 ) Rap1 sig.ling pathway (hsa04015 ) cGMP-PKG sig.ling pathway (hsa04022 ) cAMP sig.ling pathway (hsa04024 ) Chemokine sig.ling pathway (hsa04062 ) FoxO sig.ling pathway (hsa04068 ) Sphingolipid sig.ling pathway (hsa04071 ) Phospholipase D sig.ling pathway (hsa04072 ) Autophagy - animal (hsa04140 ) mTOR sig.ling pathway (hsa04150 ) PI3K-Akt sig.ling pathway (hsa04151 ) Apoptosis (hsa04210 ) Cellular senescence (hsa04218 ) Vascular smooth muscle contraction (hsa04270 ) Axon guidance (hsa04360 ) VEGF sig.ling pathway (hsa04370 ) Apelin sig.ling pathway (hsa04371 ) Focal adhesion (hsa04510 ) Gap junction (hsa04540 ) Sig.ling pathways regulating pluripotency of stem cells (hsa04550 ) Neutrophil extracellular trap formation (hsa04613 ) C-type lectin receptor sig.ling pathway (hsa04625 ) JAK-STAT sig.ling pathway (hsa04630 ) .tural killer cell mediated cytotoxicity (hsa04650 ) T cell receptor sig.ling pathway (hsa04660 ) B cell receptor sig.ling pathway (hsa04662 ) Fc epsilon RI sig.ling pathway (hsa04664 ) Fc gamma R-mediated phagocytosis (hsa04666 ) Long-term potentiation (hsa04720 ) Neurotrophin sig.ling pathway (hsa04722 ) Serotonergic sy.pse (hsa04726 ) Long-term depression (hsa04730 ) Regulation of actin cytoskeleton (hsa04810 ) Insulin sig.ling pathway (hsa04910 ) GnRH sig.ling pathway (hsa04912 ) Progesterone-mediated oocyte maturation (hsa04914 ) Estrogen sig.ling pathway (hsa04915 ) Melanogenesis (hsa04916 ) Prolactin sig.ling pathway (hsa04917 ) Thyroid hormone sig.ling pathway (hsa04919 ) Oxytocin sig.ling pathway (hsa04921 ) Relaxin sig.ling pathway (hsa04926 ) Parathyroid hormone synthesis, secretion and action (hsa04928 ) GnRH secretion (hsa04929 ) Growth hormone synthesis, secretion and action (hsa04935 ) Alzheimer disease (hsa05010 ) Pathways of neurodegeneration - multiple diseases (hsa05022 ) Alcoholism (hsa05034 ) Salmonella infection (hsa05132 ) Tuberculosis (hsa05152 ) Hepatitis C (hsa05160 ) Hepatitis B (hsa05161 ) Human cytomegalovirus infection (hsa05163 ) Influenza A (hsa05164 ) Human papillomavirus infection (hsa05165 ) Kaposi sarcoma-associated herpesvirus infection (hsa05167 ) Human immunodeficiency virus 1 infection (hsa05170 ) Pathways in cancer (hsa05200 ) Proteoglycans in cancer (hsa05205 ) MicroR.s in cancer (hsa05206 ) Chemical carcinogenesis - receptor activation (hsa05207 ) Chemical carcinogenesis - reactive oxygen species (hsa05208 ) Colorectal cancer (hsa05210 ) Re.l 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 ) Breast cancer (hsa05224 ) Hepatocellular carcinoma (hsa05225 ) Gastric cancer (hsa05226 ) Central carbon metabolism in cancer (hsa05230 ) Choline metabolism in cancer (hsa05231 ) PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235 )
Reactome Pathway	Rap1 signalling (R-HSA-392517 ) GP1b-IX-V activation signalling (R-HSA-430116 ) 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 ) Signaling by moderate kinase activity BRAF mutants (R-HSA-6802946 ) Signaling by high-kinase activity BRAF mutants (R-HSA-6802948 ) Signaling by BRAF and RAF1 fusions (R-HSA-6802952 ) Paradoxical activation of RAF signaling by kinase inactive BRAF (R-HSA-6802955 ) Signaling downstream of RAS mutants (R-HSA-9649948 ) Signaling by RAF1 mutants (R-HSA-9656223 ) SHOC2 M1731 mutant abolishes MRAS complex function (R-HSA-9726840 ) Gain-of-function MRAS complexes activate RAF signaling (R-HSA-9726842 ) IFNG signaling activates MAPKs (R-HSA-9732724 ) Stimuli-sensing channels (R-HSA-2672351 )

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Noonan syndrome	DIS7Q7DN	Definitive	Autosomal dominant	[1]
Noonan syndrome 5	DISSH144	Definitive	Autosomal dominant	[2]
Dilated cardiomyopathy 1NN	DIS68KSY	Strong	Autosomal dominant	[3]
LEOPARD syndrome 2	DISOQEB7	Strong	Autosomal dominant	[4]
Noonan syndrome with multiple lentigines	DIS014D0	Supportive	Autosomal dominant	[5]
Obsolete familial isolated dilated cardiomyopathy	DIS4FXO4	Supportive	Autosomal dominant	[3]
Cardiofaciocutaneous syndrome	DISZJKSC	Disputed	Autosomal dominant	[1]
Costello syndrome	DISXVJH3	Disputed	Autosomal dominant	[1]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	RAF proto-oncogene serine/threonine-protein kinase (RAF1) decreases the response to substance of Cisplatin.	[53]
Cholecalciferol	DMGU74E	Approved	RAF proto-oncogene serine/threonine-protein kinase (RAF1) increases the response to substance of Cholecalciferol.	[54]
Afimoxifene	DMFORDT	Phase 2	RAF proto-oncogene serine/threonine-protein kinase (RAF1) decreases the response to substance of Afimoxifene.	[55]
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37 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[9]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[10]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[13]
Testosterone	DM7HUNW	Approved	Testosterone increases the activity of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[14]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[16]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[18]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[19]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[20]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[21]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[22]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[23]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[24]
Nicotine	DMWX5CO	Approved	Nicotine increases the activity of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[26]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[27]
Simvastatin	DM30SGU	Approved	Simvastatin decreases the activity of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[28]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[29]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the activity of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[30]
Docetaxel	DMDI269	Approved	Docetaxel increases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[31]
Lovastatin	DM9OZWQ	Approved	Lovastatin decreases the activity of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[28]
Romidepsin	DMT5GNL	Approved	Romidepsin decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[32]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[34]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[35]
Tanespimycin	DMNLQHK	Phase 2	Tanespimycin decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[36]
Adaphostin	DM16QSG	Phase 1	Adaphostin decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[38]
PMID26882240-Compound-32	DMJS4RP	Patented	PMID26882240-Compound-32 decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[42]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[43]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[44]
EMODIN	DMAEDQG	Terminated	EMODIN decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[45]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[46]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the activity of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[26]
DEMETHOXYCURCUMIN	DMO5UGV	Investigative	DEMETHOXYCURCUMIN decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[49]
Eckol	DMIVY0Q	Investigative	Eckol decreases the activity of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[51]
PD173074	DMP0N4U	Investigative	PD173074 decreases the expression of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[52]
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⏷ Show the Full List of 37 Drug(s)

12 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[7]
Progesterone	DMUY35B	Approved	Progesterone decreases the phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[17]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[25]
Hydroxyflutamide	DMGIZF5	Approved	Hydroxyflutamide increases the phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[33]
Genistein	DM0JETC	Phase 2/3	Genistein increases the phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[37]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[40]
PMID26560530-Compound-35	DMO36RL	Patented	PMID26560530-Compound-35 decreases the phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[41]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[40]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[47]
Lead acetate	DML0GZ2	Investigative	Lead acetate increases the phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[48]
Naringin	DM4DG1Y	Investigative	Naringin increases the phosphorylation of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[50]
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⏷ Show the Full List of 12 Drug(s)

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Marinol	DM70IK5	Approved	Marinol increases the localization of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[15]
PU-H71	DMIYHAW	Phase 1	PU-H71 increases the degradation of RAF proto-oncogene serine/threonine-protein kinase (RAF1).	[39]
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