Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWF84QT)

• DOT Name: E3 ubiquitin-protein ligase MARCHF9 (MARCHF9)
• Synonyms: EC 2.3.2.27; Membrane-associated RING finger protein 9; Membrane-associated RING-CH protein IX; MARCH-IX; RING finger protein 179; RING-type E3 ubiquitin transferase MARCHF9
• Gene Name: MARCHF9
• Related Disease:
  OPTN-related open angle glaucoma
  Acute myocardial infarction
  Adult glioblastoma
  Advanced cancer
  Esophageal squamous cell carcinoma
  Glioblastoma multiforme
  Lung adenocarcinoma
  Neoplasm
  Schizophrenia
  Meningitis
• UniProt ID: MARH9_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF12906
• Sequence:
  MLKSRLRMFLNELKLLVLTGGGRPRAEPQPRGGRGGGCGWAPFAGCSTRDGDGDEEEYYG
  SEPRARGLAGDKEPRAGPLPPPAPPLPPPGALDALSLSSSLDSGLRTPQCRICFQGPEQG
  ELLSPCRCDGSVRCTHQPCLIRWISERGSWSCELCYFKYQVLAISTKNPLQWQAISLTVI
  EKVQIAAIVLGSLFLVASISWLIWSSLSPSAKWQRQDLLFQICYGMYGFMDVVCIGLIIH
  EGSSVYRIFKRWQAVNQQWKVLNYDKTKDIGGDAGGGTAGKSGPRNSRTGPTSGATSRPP
  AAQRMRTLLPQRCGYTILHLLGQLRPPDARSSSHSGREVVMRVTTV
• Function: E3 ubiquitin-protein ligase that may mediate ubiquitination of MHC-I, CD4 and ICAM1, and promote their subsequent endocytosis and sorting to lysosomes via multivesicular bodies. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfer the ubiquitin to targeted substrates.
• Tissue Specificity: Ubiquitously expressed.

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
OPTN-related open angle glaucoma	DISDR98A	Definitive	Biomarker	[1]
Acute myocardial infarction	DISE3HTG	Strong	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Strong	Genetic Variation	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[3]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Schizophrenia	DISSRV2N	Strong	Biomarker	[6]
Meningitis	DISQABAA	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of E3 ubiquitin-protein ligase MARCHF9 (MARCHF9).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase MARCHF9 (MARCHF9).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of E3 ubiquitin-protein ligase MARCHF9 (MARCHF9).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of E3 ubiquitin-protein ligase MARCHF9 (MARCHF9).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of E3 ubiquitin-protein ligase MARCHF9 (MARCHF9).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of E3 ubiquitin-protein ligase MARCHF9 (MARCHF9).	[12]

References

• [1] Association of WDR36 polymorphisms with primary open angle glaucoma: A systematic review and meta-analysis.Medicine (Baltimore). 2017 Jun;96(26):e7291. doi: 10.1097/MD.0000000000007291.
• [2] Biodegradable polymer sirolimus-eluting stents versus durable polymer everolimus-eluting stents in patients with ST-segment elevation myocardial infarction (BIOSTEMI): a single-blind, prospective, randomised superiority trial.Lancet. 2019 Oct 5;394(10205):1243-1253. doi: 10.1016/S0140-6736(19)31877-X. Epub 2019 Sep 2.
• [3] Computational Characterization of Suppressive Immune Microenvironments in Glioblastoma.Cancer Res. 2018 Oct 1;78(19):5574-5585. doi: 10.1158/0008-5472.CAN-17-3714. Epub 2018 Jun 19.
• [4] Dysphagia predict the response to second cycle neoadjuvant chemotherapy in first cycle no response esophageal carcinoma.J Thorac Dis. 2019 Oct;11(10):4135-4143. doi: 10.21037/jtd.2019.10.02.
• [5] MARCH9 Suppresses Lung Adenocarcinoma Progression by Downregulating ICAM-1.Cell Physiol Biochem. 2018;50(1):92-107. doi: 10.1159/000493961. Epub 2018 Oct 2.
• [6] Advancing drug discovery for schizophrenia.Ann N Y Acad Sci. 2011 Oct;1236:30-43. doi: 10.1111/j.1749-6632.2011.06216.x.
• [7] Adjunctive sertraline for HIV-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial.Lancet Infect Dis. 2019 Aug;19(8):843-851. doi: 10.1016/S1473-3099(19)30127-6.
• [8] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [9] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] 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.
• [13] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.