Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1K7DKB)

• DOT Name: Ligand-dependent corepressor (LCOR)
• Synonyms: LCoR; Mblk1-related protein 2
• Gene Name: LCOR
• Related Disease:
  Generalized resistance to thyroid hormone
  Arteriosclerosis
  Atherosclerosis
  Breast neoplasm
  Fatty liver disease
  Neoplasm
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
• UniProt ID: LCOR_HUMAN
• PDB ID: 2COB; 6V3X; 6V3Y
• Pfam ID: PF05225
• Sequence:
  MQRMIQQFAAEYTSKNSSTQDPSQPNSTKNQSLPKASPVTTSPTAATTQNPVLSKLLMAD
  QDSPLDLTVRKSQSEPSEQDGVLDLSTKKSPCAGSTSLSHSPGCSSTQGNGRPGRPSQYR
  PDGLRSGDGVPPRSLQDGTREGFGHSTSLKVPLARSLQISEELLSRNQLSTAASLGPSGL
  QNHGQHLILSREASWAKPHYEFNLSRMKFRGNGALSNISDLPFLAENSAFPKMALQAKQD
  GKKDVSHSSPVDLKIPQVRGMDLSWESRTGDQYSYSSLVMGSQTESALSKKLRAILPKQS
  RKSMLDAGPDSWGSDAEQSTSGQPYPTSDQEGDPGSKQPRKKRGRYRQYNSEILEEAISV
  VMSGKMSVSKAQSIYGIPHSTLEYKVKERLGTLKNPPKKKMKLMRSEGPDVSVKIELDPQ
  GEAAQSANESKNE
• Function: May act as transcription activator that binds DNA elements with the sequence 5'-CCCTATCGATCGATCTCTACCT-3'. Repressor of ligand-dependent transcription activation by target nuclear receptors. Repressor of ligand-dependent transcription activation by ESR1, ESR2, NR3C1, PGR, RARA, RARB, RARG, RXRA and VDR.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Polycomb repressive complex (hsa03083)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Generalized resistance to thyroid hormone	DIS4TOK0	Definitive	Biomarker	[1]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[2]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Fatty liver disease	DIS485QZ	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[6]
Prostate cancer	DISF190Y	moderate	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	moderate	Altered Expression	[7]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[5]
Breast cancer	DIS7DPX1	Limited	Biomarker	[5]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[5]

15 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 Ligand-dependent corepressor (LCOR).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Ligand-dependent corepressor (LCOR).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Ligand-dependent corepressor (LCOR).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Ligand-dependent corepressor (LCOR).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ligand-dependent corepressor (LCOR).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Ligand-dependent corepressor (LCOR).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ligand-dependent corepressor (LCOR).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Ligand-dependent corepressor (LCOR).	[15]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ligand-dependent corepressor (LCOR).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ligand-dependent corepressor (LCOR).	[17]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Ligand-dependent corepressor (LCOR).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Ligand-dependent corepressor (LCOR).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ligand-dependent corepressor (LCOR).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Ligand-dependent corepressor (LCOR).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Ligand-dependent corepressor (LCOR).	[24]

4 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 Ligand-dependent corepressor (LCOR).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Ligand-dependent corepressor (LCOR).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ligand-dependent corepressor (LCOR).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Ligand-dependent corepressor (LCOR).	[22]

References

• [1] Thyroid hormone receptor-beta mutations conferring hormone resistance and reduced corepressor release exhibit decreased stability in the N-terminal ligand-binding domain.Mol Endocrinol. 2003 Jan;17(1):107-16. doi: 10.1210/me.2002-0097.
• [2] Dicer in Macrophages Prevents Atherosclerosis by Promoting Mitochondrial Oxidative Metabolism.Circulation. 2018 Oct 30;138(18):2007-2020. doi: 10.1161/CIRCULATIONAHA.117.031589.
• [3] Normal and cancerous mammary stem cells evade interferon-induced constraint through the miR-199a-LCOR axis.Nat Cell Biol. 2017 Jun;19(6):711-723. doi: 10.1038/ncb3533. Epub 2017 May 22.
• [4] Ligand-dependent corepressor acts as a novel corepressor of thyroid hormone receptor and represses hepatic lipogenesis in mice.J Hepatol. 2012 Jan;56(1):248-54. doi: 10.1016/j.jhep.2011.07.014. Epub 2011 Aug 7.
• [5] Importance of RIP140 and LCoR Sub-Cellular Localization for Their Association With Breast Cancer Aggressiveness and Patient Survival.Transl Oncol. 2018 Oct;11(5):1090-1096. doi: 10.1016/j.tranon.2018.06.006. Epub 2018 Jul 11.
• [6] The CCND1 c.870G>A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma.Nat Genet. 2013 May;45(5):522-525. doi: 10.1038/ng.2583. Epub 2013 Mar 17.
• [7] Ligand-dependent corepressor acts as a novel androgen receptor corepressor, inhibits prostate cancer growth, and is functionally inactivated by the Src protein kinase.J Biol Chem. 2011 Oct 28;286(43):37108-17. doi: 10.1074/jbc.M111.292771. Epub 2011 Aug 19.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [10] 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.
• [11] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [14] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [15] 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.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [22] 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.
• [23] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [24] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.