Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKZQT0R)

• DOT Name: Mediator of RNA polymerase II transcription subunit 23 (MED23)
• Synonyms: Activator-recruited cofactor 130 kDa component; ARC130; Cofactor required for Sp1 transcriptional activation subunit 3; CRSP complex subunit 3; Mediator complex subunit 23; Protein sur-2 homolog; hSur-2; Transcriptional coactivator CRSP130; Vitamin D3 receptor-interacting protein complex 130 kDa component; DRIP130
• Gene Name: MED23
• Related Disease:
  Alzheimer disease
  Angina pectoris
  Breast cancer
  Breast carcinoma
  Cardiovascular disease
  Congestive heart failure
  Coronary vasospasm
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Herpes simplex infection
  High blood pressure
  Hypertrichosis
  Hypertrichosis lanuginosa congenita
  Intellectual disability
  Intellectual disability, autosomal recessive 18
  Lung cancer
  Lung carcinoma
  Metastatic malignant neoplasm
  Metastatic melanoma
  Myocardial infarction
  Myocardial ischemia
  Neoplasm
  Non-insulin dependent diabetes
  Non-small-cell lung cancer
  Retinoblastoma
  Arginase 1 deficiency
  Hypertrichotic osteochondrodysplasia Cantu type
  Syndromic intellectual disability
  Autosomal recessive non-syndromic intellectual disability
  Advanced cancer
• UniProt ID: MED23_HUMAN
• PDB ID: 6H02; 7EMF; 7ENA; 7ENC; 7ENJ; 7LBM; 8GXQ; 8GXS
• Pfam ID: PF11573
• Sequence:
  METQLQSIFEEVVKTEVIEEAFPGMFMDTPEDEKTKLISCLGAFRQFWGGLSQESHEQCI
  QWIVKFIHGQHSPKRISFLYDCLAMAVETGLLPPRLVCESLINSDTLEWERTQLWALTFK
  LVRKIIGGVDYKGVRDLLKVILEKILTIPNTVSSAVVQQLLAAREVIAYILERNACLLPA
  YFAVTEIRKLYPEGKLPHWLLGNLVSDFVDTFRPTARINSICGRCSLLPVVNNSGAICNS
  WKLDPATLRFPLKGLLPYDKDLFEPQTALLRYVLEQPYSRDMVCNMLGLNKQHKQRCPVL
  EDQLVDLVVYAMERSETEEKFDDGGTSQLLWQHLSSQLIFFVLFQFASFPHMVLSLHQKL
  AGRGLIKGRDHLMWVLLQFISGSIQKNALADFLPVMKLFDLLYPEKEYIPVPDINKPQST
  HAFAMTCIWIHLNRKAQNDNSKLQIPIPHSLRLHHEFLQQSLRNKSLQMNDYKIALLCNA
  YSTNSECFTLPMGALVETIYGNGIMRIPLPGTNCMASGSITPLPMNLLDSLTVHAKMSLI
  HSIATRVIKLAHAKSSVALAPALVETYSRLLVYMEIESLGIKGFISQLLPTVFKSHAWGI
  LHTLLEMFSYRMHHIQPHYRVQLLSHLHTLAAVAQTNQNQLHLCVESTALRLITALGSSE
  VQPQFTRFLSDPKTVLSAESEELNRALILTLARATHVTDFFTGSDSIQGTWCKDILQTIM
  SFTPHNWASHTLSCFPGPLQAFFKQNNVPQESRFNLKKNVEEEYRKWKSMSNENDIITHF
  SMQGSPPLFLCLLWKMLLETDHINQIGYRVLERIGARALVAHVRTFADFLVYEFSTSAGG
  QQLNKCIEILNDMVWKYNIVTLDRLILCLAMRSHEGNEAQVCYFIIQLLLLKPNDFRNRV
  SDFVKENSPEHWLQNDWHTKHMNYHKKYPEKLYFEGLAEQVDPPVQIQSPYLPIYFGNVC
  LRFLPVFDIVIHRFLELLPVSKSLETLLDHLGGLYKFHDRPVTYLYNTLHYYEMHLRDRA
  FLKRKLVHAIIGSLKDNRPQGWCLSDTYLKCAMNAREENPWVPDDTYYCRLIGRLVDTMA
  GKSPGPFPNCDWRFNEFPNPAAHALHVTCVELMALAVSGKEVGNALLNVVLKSQPLVPRE
  NITAWMNAIGLIITALPEPYWIVLHDRIVSVISSPSLTSETEWVGYPFRLFDFTACHQSY
  SEMSCSYTLALAHAVWHHSSIGQLSLIPKFLTEVLLPIVKTEFQLLYVYHLVGPFLQRFQ
  QERTRCMIEIGVAFYDMLLNVDQCSTHLNYMDPICDFLYHMKYMFTGDSVKEQVEKIICN
  LKPALKLRLRFITHISKMEPAAVPPQAMNSGSPAPQSNQVPVSLPVTQ
• Function: Required for transcriptional activation subsequent to the assembly of the pre-initiation complex. Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors. Required for transcriptional activation by adenovirus E1A protein. Required for ELK1-dependent transcriptional activation in response to activated Ras signaling.
• Reactome Pathway:
  Generic Transcription Pathway (R-HSA-212436)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

30 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Angina pectoris	DISCLMC4	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[4]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[5]
Coronary vasospasm	DISSHV10	Strong	Biomarker	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[8]
High blood pressure	DISY2OHH	Strong	Biomarker	[2]
Hypertrichosis	DISZUK5W	Strong	Biomarker	[9]
Hypertrichosis lanuginosa congenita	DISX1C1I	Strong	Biomarker	[10]
Intellectual disability	DISMBNXP	Strong	Biomarker	[11]
Intellectual disability, autosomal recessive 18	DIS0HQDG	Strong	Autosomal recessive	[12]
Lung cancer	DISCM4YA	Strong	Altered Expression	[13]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[13]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[14]
Metastatic melanoma	DISSL43L	Strong	Altered Expression	[14]
Myocardial infarction	DIS655KI	Strong	Biomarker	[15]
Myocardial ischemia	DISFTVXF	Strong	Genetic Variation	[15]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[16]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[17]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[7]
Arginase 1 deficiency	DISAGUMY	moderate	Genetic Variation	[18]
Hypertrichotic osteochondrodysplasia Cantu type	DISI9W4I	moderate	Genetic Variation	[19]
Syndromic intellectual disability	DISH7SDF	Moderate	Autosomal recessive	[20]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[12]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Mediator of RNA polymerase II transcription subunit 23 (MED23).	[22]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Mediator of RNA polymerase II transcription subunit 23 (MED23).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Mediator of RNA polymerase II transcription subunit 23 (MED23).	[24]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Mediator of RNA polymerase II transcription subunit 23 (MED23).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Mediator of RNA polymerase II transcription subunit 23 (MED23).	[26]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Mediator of RNA polymerase II transcription subunit 23 (MED23).	[27]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Mediator of RNA polymerase II transcription subunit 23 (MED23).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Mediator of RNA polymerase II transcription subunit 23 (MED23).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Mediator of RNA polymerase II transcription subunit 23 (MED23).	[30]

References

• [1] Modulation of Immune Responses toHerpes Simplex Virus Type1 by IFNL3 and IRF7 Polymorphisms: AStudy inAlzheimer's Disease.J Alzheimers Dis. 2017;60(3):1055-1063. doi: 10.3233/JAD-170520.
• [2] Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K(ATP) channels.J Clin Invest. 2002 Jul;110(2):203-8. doi: 10.1172/JCI15672.
• [3] MED23 in endocrinotherapy for breast cancer.Oncol Lett. 2017 Jun;13(6):4679-4684. doi: 10.3892/ol.2017.6036. Epub 2017 Apr 13.
• [4] Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine.Circ Cardiovasc Genet. 2014 Dec;7(6):864-72. doi: 10.1161/CIRCGENETICS.113.000264. Epub 2014 Sep 21.
• [5] Effects of KATP channel openers diazoxide and pinacidil in coronary-perfused atria and ventricles from failing and non-failing human hearts.J Mol Cell Cardiol. 2011 Aug;51(2):215-25. doi: 10.1016/j.yjmcc.2011.04.016. Epub 2011 May 7.
• [6] Downregulation of MED23 promoted the tumorigenecity of esophageal squamous cell carcinoma.Mol Carcinog. 2014 Oct;53(10):833-40. doi: 10.1002/mc.22041. Epub 2013 Apr 27.
• [7] Mediator subunit 23 overexpression as a novel target for suppressing proliferation and tumorigenesis in hepatocellular carcinoma.J Gastroenterol Hepatol. 2015 Jun;30(6):1094-103. doi: 10.1111/jgh.12923.
• [8] A systematic analysis of host factors reveals a Med23-interferon- regulatory axis against herpes simplex virus type 1 replication.PLoS Pathog. 2013;9(8):e1003514. doi: 10.1371/journal.ppat.1003514. Epub 2013 Aug 8.
• [9] Mutation of KCNJ8 in a patient with Cant syndrome with unique vascular abnormalities - support for the role of K(ATP) channels in this condition. Eur J Med Genet. 2013 Dec;56(12):678-82. doi: 10.1016/j.ejmg.2013.09.009. Epub 2013 Oct 28.
• [10] Topical sulfonylurea as a novel therapy for hypertrichosis secondary to diazoxide, and potentially for other conditions with excess hair growth.Med Hypotheses. 2015 Dec;85(6):969-71. doi: 10.1016/j.mehy.2015.08.025. Epub 2015 Sep 5.
• [11] MED23-associated intellectual disability in a non-consanguineous family.Am J Med Genet A. 2015 Jun;167(6):1374-80. doi: 10.1002/ajmg.a.37047. Epub 2015 Apr 2.
• [12] MED23 mutation links intellectual disability to dysregulation of immediate early gene expression. Science. 2011 Aug 26;333(6046):1161-3. doi: 10.1126/science.1206638.
• [13] Selective requirement for Mediator MED23 in Ras-active lung cancer.Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):E2813-22. doi: 10.1073/pnas.1204311109. Epub 2012 Sep 17.
• [14] Transcriptional regulation of KiSS-1 gene expression in metastatic melanoma by specificity protein-1 and its coactivator DRIP-130.Oncogene. 2007 Mar 15;26(12):1739-47. doi: 10.1038/sj.onc.1209963. Epub 2006 Sep 11.
• [15] Effect of l-arginine, asymmetric dimethylarginine, and symmetric dimethylarginine on ischemic heart disease risk: A Mendelian randomization study.Am Heart J. 2016 Dec;182:54-61. doi: 10.1016/j.ahj.2016.07.021. Epub 2016 Aug 26.
• [16] Genome-wide association analyses identify 143 risk variants and putative regulatory mechanisms for type 2 diabetes.Nat Commun. 2018 Jul 27;9(1):2941. doi: 10.1038/s41467-018-04951-w.
• [17] Upregulation of mediator MED23 in non-small-cell lung cancer promotes the growth, migration, and metastasis of cancer cells.Tumour Biol. 2014 Dec;35(12):12005-13. doi: 10.1007/s13277-014-2499-3. Epub 2014 Oct 2.
• [18] Clinical phenotype, biochemical profile, and treatment in 19 patients with arginase 1 deficiency.J Inherit Metab Dis. 2016 May;39(3):331-340. doi: 10.1007/s10545-016-9928-y. Epub 2016 Apr 1.
• [19] Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity.J Clin Invest. 2020 Mar 2;130(3):1116-1121. doi: 10.1172/JCI130571.
• [20] 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.
• [21] MEGSA: A Powerful and Flexible Framework for Analyzing Mutual Exclusivity of Tumor Mutations.Am J Hum Genet. 2016 Mar 3;98(3):442-455. doi: 10.1016/j.ajhg.2015.12.021. Epub 2016 Feb 18.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [24] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [25] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [26] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [27] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [30] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.