Details of Drug Off-Target (DOT)

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

• DOT Name: Ras-related protein M-Ras (MRAS)
• Synonyms: EC 3.6.5.2; Ras-related protein R-Ras3
• Gene Name: MRAS
• Related Disease:
  Coronary atherosclerosis
  Neoplasm
  Noonan syndrome 11
  Acute coronary syndrome
  Advanced cancer
  Cardiovascular disease
  Hypertrophic cardiomyopathy
  Narcolepsy
  Plasma cell myeloma
  Carotid artery disease
  Gastric cancer
  Noonan syndrome
  Stomach cancer
  Colorectal carcinoma
  Myocardial infarction
  Nasopharyngeal carcinoma
  Non-insulin dependent diabetes
• UniProt ID: RASM_HUMAN
• PDB ID: 7SD0; 7TVF; 7TXH; 7UPI
• EC Number: 3.6.5.2
• Pfam ID: PF00071
• Sequence:
  MATSAVPSDNLPTYKLVVVGDGGVGKSALTIQFFQKIFVPDYDPTIEDSYLKHTEIDNQW
  AILDVLDTAGQEEFSAMREQYMRTGDGFLIVYSVTDKASFEHVDRFHQLILRVKDRESFP
  MILVANKVDLMHLRKITREQGKEMATKHNIPYIETSAKDPPLNVDKAFHDLVRVIRQQIP
  EKSQKKKKKTKWRGDRATGTHKLQCVIL
• Function: Serves as an important signal transducer for a novel upstream stimuli in controlling cell proliferation. Activates the MAP kinase pathway.
• Tissue Specificity: Expression highly restricted to the brain and heart.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Rap1 sig.ling pathway (hsa04015)
  Phospholipase D sig.ling pathway (hsa04072)
  Mitophagy - animal (hsa04137)
  Autophagy - animal (hsa04140)
  Cellular senescence (hsa04218)
  Apelin sig.ling pathway (hsa04371)
  C-type lectin receptor sig.ling pathway (hsa04625)
  Regulation of actin cytoskeleton (hsa04810)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  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

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary atherosclerosis	DISKNDYU	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[2]
Noonan syndrome 11	DISUQMTP	Definitive	Autosomal dominant	[3]
Acute coronary syndrome	DIS7DYEW	Strong	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[5]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[6]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[7]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[8]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[9]
Carotid artery disease	DISLRVLT	moderate	Biomarker	[10]
Gastric cancer	DISXGOUK	moderate	Genetic Variation	[11]
Noonan syndrome	DIS7Q7DN	Moderate	Autosomal dominant	[12]
Stomach cancer	DISKIJSX	moderate	Genetic Variation	[11]
Colorectal carcinoma	DIS5PYL0	Disputed	Genetic Variation	[13]
Myocardial infarction	DIS655KI	Limited	Genetic Variation	[4]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[14]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Biomarker	[15]

2 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 Ras-related protein M-Ras (MRAS).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Ras-related protein M-Ras (MRAS).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras-related protein M-Ras (MRAS).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Ras-related protein M-Ras (MRAS).	[18]
Arsenic	DMTL2Y1	Approved	Arsenic affects the expression of Ras-related protein M-Ras (MRAS).	[19]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Ras-related protein M-Ras (MRAS).	[20]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Ras-related protein M-Ras (MRAS).	[21]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Ras-related protein M-Ras (MRAS).	[22]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Ras-related protein M-Ras (MRAS).	[20]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Ras-related protein M-Ras (MRAS).	[23]
Febuxostat	DMDEXQ0	Approved	Febuxostat increases the expression of Ras-related protein M-Ras (MRAS).	[24]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Ras-related protein M-Ras (MRAS).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Ras-related protein M-Ras (MRAS).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Ras-related protein M-Ras (MRAS).	[28]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Ras-related protein M-Ras (MRAS).	[29]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Ras-related protein M-Ras (MRAS).	[30]

References

• [1] Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease.Nat Genet. 2011 Mar 6;43(4):333-8. doi: 10.1038/ng.784.
• [2] An MRAS, SHOC2, and SCRIB complex coordinates ERK pathway activation with polarity and tumorigenic growth.Mol Cell. 2013 Dec 12;52(5):679-92. doi: 10.1016/j.molcel.2013.10.004. Epub 2013 Nov 7.
• [3] Severe Noonan syndrome phenotype associated with a germline Q71R MRAS variant: a recurrent substitution in RAS homologs in various cancers. Am J Med Genet A. 2019 Aug;179(8):1628-1630. doi: 10.1002/ajmg.a.61261. Epub 2019 Jun 7.
• [4] MRAS gene marker rs9818870 is not associated with acute coronary syndrome in the Czech population and does not predict mortality in males after acute coronary syndrome.Adv Clin Exp Med. 2017 Nov;26(8):1213-1217. doi: 10.17219/acem/67460.
• [5] MRAS: A Close but Understudied Member of the RAS Family.Cold Spring Harb Perspect Med. 2018 Dec 3;8(12):a033621. doi: 10.1101/cshperspect.a033621.
• [6] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [7] Activating MRAS mutations cause Noonan syndrome associated with hypertrophic cardiomyopathy.Hum Mol Genet. 2020 Jul 21;29(11):1772-1783. doi: 10.1093/hmg/ddz108.
• [8] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [9] Translocation t(11;14)(q13;q32) is the hallmark of IgM, IgE, and nonsecretory multiple myeloma variants.Blood. 2003 Feb 15;101(4):1570-1. doi: 10.1182/blood-2002-08-2436. Epub 2002 Oct 3.
• [10] New susceptibility locus for coronary artery disease on chromosome 3q22.3.Nat Genet. 2009 Mar;41(3):280-2. doi: 10.1038/ng.307. Epub 2009 Feb 8.
• [11] Muscle RAS oncogene homolog (MRAS) recurrent mutation in Borrmann type IV gastric cancer.Cancer Med. 2017 Jan;6(1):235-244. doi: 10.1002/cam4.959. Epub 2016 Nov 28.
• [12] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [13] A two-phase case-control study for colorectal cancer genetic susceptibility: candidate genes from chromosomal regions 9q22 and 3q22.Br J Cancer. 2011 Sep 6;105(6):870-5. doi: 10.1038/bjc.2011.296. Epub 2011 Aug 2.
• [14] Human Ribosomal Proteins RPeL27, RPeL43, and RPeL41 Are Upregulated in Nasopharyngeal Carcinoma Cell Lines.Dis Markers. 2016;2016:5179594. doi: 10.1155/2016/5179594. Epub 2016 Nov 28.
• [15] Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease.Nat Genet. 2017 Oct;49(10):1450-1457. doi: 10.1038/ng.3943. Epub 2017 Sep 4.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] Drinking-water arsenic exposure modulates gene expression in human lymphocytes from a U.S. population. Environ Health Perspect. 2008 Apr;116(4):524-31. doi: 10.1289/ehp.10861.
• [20] 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.
• [21] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [22] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [23] Ouabain impairs cell migration, and invasion and alters gene expression of human osteosarcoma U-2 OS cells. Environ Toxicol. 2017 Nov;32(11):2400-2413. doi: 10.1002/tox.22453. Epub 2017 Aug 10.
• [24] Febuxostat Increases Ventricular Arrhythmogenesis Through Calcium Handling Dysregulation in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Toxicol Sci. 2022 Sep 24;189(2):216-224. doi: 10.1093/toxsci/kfac073.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] 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.
• [27] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [28] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [29] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [30] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.