Details of Drug Off-Target (DOT)

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

• DOT Name: REST corepressor 1 (RCOR1)
• Synonyms: Protein CoREST
• Gene Name: RCOR1
• Related Disease:
  Acute myelogenous leukaemia
  Adult lymphoma
  Advanced cancer
  Aicardi-Goutieres syndrome
  Alzheimer disease
  B-cell lymphoma
  Ciliopathy
  Colon carcinoma
  Colonic neoplasm
  FG syndrome
  Herpes simplex infection
  Huntington disease
  Joubert syndrome
  Lung carcinoma
  Lymphoma
  Pediatric lymphoma
  Triple negative breast cancer
  X-linked intellectual disability
  X-linked intellectual disability with marfanoid habitus
  Colorectal carcinoma
  Breast cancer
  Breast carcinoma
  Colon cancer
• UniProt ID: RCOR1_HUMAN
• PDB ID: 2IW5 ; 2UXN ; 2UXX ; 2V1D ; 2X0L ; 2XAF ; 2XAG ; 2XAH ; 2XAJ ; 2XAQ ; 2XAS ; 2Y48 ; 3ZMS ; 3ZMT ; 3ZMU ; 3ZMV ; 3ZMZ ; 3ZN0 ; 3ZN1 ; 4BAY ; 4KUM ; 4UV8 ; 4UV9 ; 4UVA ; 4UVB ; 4UVC ; 4UXN ; 4XBF ; 5H6Q ; 5H6R ; 5L3B ; 5L3C ; 5L3D ; 5L3E ; 5L3F ; 5L3G ; 5LBQ ; 5LGN ; 5LGT ; 5LGU ; 5LHG ; 5LHH ; 5LHI ; 5X60 ; 5YJB ; 6K3E ; 6KGK ; 6KGL ; 6KGM ; 6KGN ; 6S35 ; 6TE1 ; 6TUY ; 6VYP ; 6W4K ; 6WC6 ; 7CDC ; 7CDD ; 7CDE ; 7CDF ; 7CDG ; 7ZRY
• Pfam ID: PF01448 ; PF00249 ; PF20878
• Sequence:
  MPAMVEKGPEVSGKRRGRNNAAASASAAAASAAASAACASPAATAASGAAASSASAAAAS
  AAAAPNNGQNKSLAAAAPNGNSSSNSWEEGSSGSSSDEEHGGGGMRVGPQYQAVVPDFDP
  AKLARRSQERDNLGMLVWSPNQNLSEAKLDEYIAIAKEKHGYNMEQALGMLFWHKHNIEK
  SLADLPNFTPFPDEWTVEDKVLFEQAFSFHGKTFHRIQQMLPDKSIASLVKFYYSWKKTR
  TKTSVMDRHARKQKREREESEDELEEANGNNPIDIEVDQNKESKKEVPPTETVPQVKKEK
  HSTQAKNRAKRKPPKGMFLSQEDVEAVSANATAATTVLRQLDMELVSVKRQIQNIKQTNS
  ALKEKLDGGIEPYRLPEVIQKCNARWTTEEQLLAVQAIRKYGRDFQAISDVIGNKSVVQV
  KNFFVNYRRRFNIDEVLQEWEAEHGKEETNGPSNQKPVKSPDNSIKMPEEEDEAPVLDVR
  YASAS
• Function: Essential component of the BHC complex, a corepressor complex that represses transcription of neuron-specific genes in non-neuronal cells. The BHC complex is recruited at RE1/NRSE sites by REST and acts by deacetylating and demethylating specific sites on histones, thereby acting as a chromatin modifier. In the BHC complex, it serves as a molecular beacon for the recruitment of molecular machinery, including MeCP2 and SUV39H1, that imposes silencing across a chromosomal interval. Plays a central role in demethylation of Lys-4 of histone H3 by promoting demethylase activity of KDM1A on core histones and nucleosomal substrates. It also protects KDM1A from the proteasome. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development and controls hematopoietic differentiation.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Huntington disease (hsa05016)
• Reactome Pathway:
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Potential therapeutics for SARS (R-HSA-9679191)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  HDACs deacetylate histones (R-HSA-3214815)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Biomarker	[1]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Aicardi-Goutieres syndrome	DIS1NH4X	Strong	Genetic Variation	[4]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[5]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[2]
Ciliopathy	DIS10G4I	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[7]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[8]
FG syndrome	DIS2MEFU	Strong	Biomarker	[9]
Herpes simplex infection	DISL1SAV	Strong	Altered Expression	[10]
Huntington disease	DISQPLA4	Strong	Biomarker	[5]
Joubert syndrome	DIS7P5CO	Strong	Genetic Variation	[6]
Lung carcinoma	DISTR26C	Strong	Biomarker	[11]
Lymphoma	DISN6V4S	Strong	Biomarker	[2]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[2]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[12]
X-linked intellectual disability	DISYJBY3	Strong	Genetic Variation	[9]
X-linked intellectual disability with marfanoid habitus	DISEL7RK	Strong	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	moderate	Genetic Variation	[13]
Breast cancer	DIS7DPX1	Limited	Biomarker	[14]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[14]
Colon cancer	DISVC52G	Limited	Biomarker	[7]

3 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 REST corepressor 1 (RCOR1).	[15]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of REST corepressor 1 (RCOR1).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of REST corepressor 1 (RCOR1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of REST corepressor 1 (RCOR1).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of REST corepressor 1 (RCOR1).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of REST corepressor 1 (RCOR1).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of REST corepressor 1 (RCOR1).	[19]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of REST corepressor 1 (RCOR1).	[20]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of REST corepressor 1 (RCOR1).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of REST corepressor 1 (RCOR1).	[22]

References

• [1] Targeting the GFI1/1B-CoREST Complex in Acute Myeloid Leukemia.Front Oncol. 2019 Oct 9;9:1027. doi: 10.3389/fonc.2019.01027. eCollection 2019.
• [2] An RCOR1 loss-associated gene expression signature identifies a prognostically significant DLBCL subgroup.Blood. 2015 Feb 5;125(6):959-66. doi: 10.1182/blood-2013-06-507152. Epub 2014 Nov 13.
• [3] Chromatin repressive complexes in stem cells, development, and cancer.Cell Stem Cell. 2014 Jun 5;14(6):735-51. doi: 10.1016/j.stem.2014.05.006.
• [4] Aicardi-Goutires Syndrome associated mutations of RNase H2B impair its interaction with ZMYM3 and the CoREST histone-modifying complex.PLoS One. 2019 Mar 19;14(3):e0213553. doi: 10.1371/journal.pone.0213553. eCollection 2019.
• [5] MicroRNA-22 (miR-22) overexpression is neuroprotective via general anti-apoptotic effects and may also target specific Huntington's disease-related mechanisms.PLoS One. 2013;8(1):e54222. doi: 10.1371/journal.pone.0054222. Epub 2013 Jan 17.
• [6] Whole exome sequencing identifies causative mutations in the majority of consanguineous or familial cases with childhood-onset increased renal echogenicity.Kidney Int. 2016 Feb;89(2):468-475. doi: 10.1038/ki.2015.317.
• [7] Blood transcriptional and microRNA responses to short-term exposure to disinfection by-products in a swimming pool.Environ Int. 2018 Jan;110:42-50. doi: 10.1016/j.envint.2017.10.003. Epub 2017 Nov 6.
• [8] Silencing of the DNA mismatch repair gene MLH1 induced by hypoxic stress in a pathway dependent on the histone demethylase LSD1.Cell Rep. 2014 Jul 24;8(2):501-13. doi: 10.1016/j.celrep.2014.06.035. Epub 2014 Jul 17.
• [9] Mediator links epigenetic silencing of neuronal gene expression with x-linked mental retardation.Mol Cell. 2008 Aug 8;31(3):347-59. doi: 10.1016/j.molcel.2008.05.023.
• [10] The CoREST/REST repressor is both necessary and inimical for expression of herpes simplex virus genes.mBio. 2010 Dec 28;2(1):e00313-10. doi: 10.1128/mBio.00313-10.
• [11] SWI/SNF complex is essential for NRSF-mediated suppression of neuronal genes in human nonsmall cell lung carcinoma cell lines.Oncogene. 2006 Jan 19;25(3):470-9. doi: 10.1038/sj.onc.1209068.
• [12] Lysine-Specific Histone Demethylase 1A Regulates Macrophage Polarization and Checkpoint Molecules in the Tumor Microenvironment of Triple-Negative Breast Cancer.Front Immunol. 2019 Jun 12;10:1351. doi: 10.3389/fimmu.2019.01351. eCollection 2019.
• [13] Lysine-Specific Demethylase 1 Mediates AKT Activity and Promotes Epithelial-to-Mesenchymal Transition in PIK3CA-Mutant Colorectal Cancer.Mol Cancer Res. 2020 Feb;18(2):264-277. doi: 10.1158/1541-7786.MCR-19-0748. Epub 2019 Nov 8.
• [14] TRPS1 regulates oestrogen receptor binding and histone acetylation at enhancers.Oncogene. 2018 Sep;37(39):5281-5291. doi: 10.1038/s41388-018-0312-2. Epub 2018 Jun 12.
• [15] 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.
• [16] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [17] 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.
• [18] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [19] 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.
• [20] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [23] 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.
• [24] 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.