Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZJ0FNO)

• DOT Name: Serine/threonine-protein kinase A-Raf (ARAF)
• Synonyms: EC 2.7.11.1; Proto-oncogene A-Raf; Proto-oncogene A-Raf-1; Proto-oncogene Pks
• Gene Name: ARAF
• Related Disease: Diffuse lymphatic malformation
• UniProt ID: ARAF_HUMAN
• PDB ID: 1WXM; 2MSE
• EC Number: 2.7.11.1
• Pfam ID: PF00130 ; PF07714 ; PF02196
• Sequence:
  MEPPRGPPANGAEPSRAVGTVKVYLPNKQRTVVTVRDGMSVYDSLDKALKVRGLNQDCCV
  VYRLIKGRKTVTAWDTAIAPLDGEELIVEVLEDVPLTMHNFVRKTFFSLAFCDFCLKFLF
  HGFRCQTCGYKFHQHCSSKVPTVCVDMSTNRQQFYHSVQDLSGGSRQHEAPSNRPLNELL
  TPQGPSPRTQHCDPEHFPFPAPANAPLQRIRSTSTPNVHMVSTTAPMDSNLIQLTGQSFS
  TDAAGSRGGSDGTPRGSPSPASVSSGRKSPHSKSPAEQRERKSLADDKKKVKNLGYRDSG
  YYWEVPPSEVQLLKRIGTGSFGTVFRGRWHGDVAVKVLKVSQPTAEQAQAFKNEMQVLRK
  TRHVNILLFMGFMTRPGFAIITQWCEGSSLYHHLHVADTRFDMVQLIDVARQTAQGMDYL
  HAKNIIHRDLKSNNIFLHEGLTVKIGDFGLATVKTRWSGAQPLEQPSGSVLWMAAEVIRM
  QDPNPYSFQSDVYAYGVVLYELMTGSLPYSHIGCRDQIIFMVGRGYLSPDLSKISSNCPK
  AMRRLLSDCLKFQREERPLFPQILATIELLQRSLPKIERSASEPSLHRTQADELPACLLS
  AARLVP
• Function: Involved in the transduction of mitogenic signals from the cell membrane to the nucleus. May also regulate the TOR signaling cascade. Phosphorylates PFKFB2 ; [Isoform 2]: Serves as a positive regulator of myogenic differentiation by inducing cell cycle arrest, the expression of myogenin and other muscle-specific proteins, and myotube formation.
• Tissue Specificity: Predominantly in urogenital tissues.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  Endocrine resistance (hsa01522)
  MAPK sig.ling pathway (hsa04010)
  ErbB sig.ling pathway (hsa04012)
  FoxO sig.ling pathway (hsa04068)
  Vascular smooth muscle contraction (hsa04270)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Long-term potentiation (hsa04720)
  Serotonergic sy.pse (hsa04726)
  Long-term depression (hsa04730)
  Regulation of actin cytoskeleton (hsa04810)
  Insulin sig.ling pathway (hsa04910)
  Progesterone-mediated oocyte maturation (hsa04914)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Alcoholism (hsa05034)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  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)
• Reactome Pathway:
  MAP2K and MAPK activation (R-HSA-5674135)
  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)
  RAF activation (R-HSA-5673000)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diffuse lymphatic malformation	DISOMNLC	Limited	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Serine/threonine-protein kinase A-Raf (ARAF).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Serine/threonine-protein kinase A-Raf (ARAF).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Serine/threonine-protein kinase A-Raf (ARAF).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Serine/threonine-protein kinase A-Raf (ARAF).	[14]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Serine/threonine-protein kinase A-Raf (ARAF).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Serine/threonine-protein kinase A-Raf (ARAF).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Serine/threonine-protein kinase A-Raf (ARAF).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Serine/threonine-protein kinase A-Raf (ARAF).	[6]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Serine/threonine-protein kinase A-Raf (ARAF).	[7]
Selenium	DM25CGV	Approved	Selenium increases the expression of Serine/threonine-protein kinase A-Raf (ARAF).	[8]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Serine/threonine-protein kinase A-Raf (ARAF).	[9]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Serine/threonine-protein kinase A-Raf (ARAF).	[10]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Serine/threonine-protein kinase A-Raf (ARAF).	[7]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Serine/threonine-protein kinase A-Raf (ARAF).	[11]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Serine/threonine-protein kinase A-Raf (ARAF).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Serine/threonine-protein kinase A-Raf (ARAF).	[15]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] Estrogen Regulates MAPK-Related Genes through Genomic and Nongenomic Interactions between IGF-I Receptor Tyrosine Kinase and Estrogen Receptor-Alpha Signaling Pathways in Human Uterine Leiomyoma Cells. J Signal Transduct. 2012;2012:204236. doi: 10.1155/2012/204236. Epub 2012 Oct 9.
• [6] Quercetin and Cisplatin combined treatment altered cell cycle and mitogen activated protein kinase expressions in malignant mesotelioma cells. BMC Complement Altern Med. 2016 Aug 11;16(1):281. doi: 10.1186/s12906-016-1267-x.
• [7] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [8] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [9] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [10] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [11] Ouabain at pathological concentrations might induce damage in human vascular endothelial cells. Acta Pharmacol Sin. 2006 Feb;27(2):165-72. doi: 10.1111/j.1745-7254.2006.00244.x.
• [12] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [14] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [15] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.