Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG013AX)

• DOT Name: BCL-6 corepressor (BCOR)
• Synonyms: BCoR
• Gene Name: BCOR
• Related Disease:
  Kidney neoplasm
  Microphthalmia, syndromic 2
  Acute myelogenous leukaemia
  Autoimmune disease
  B-cell neoplasm
  Brain neoplasm
  Central nervous system neoplasm
  Clear cell sarcoma
  Endometrial cancer
  Endometrial carcinoma
  Ewing sarcoma
  Glioma
  Hepatocellular carcinoma
  Kidney cancer
  leukaemia
  Leukemia
  Medulloblastoma
  Microphthalmia
  Microphthalmia, syndromic 1
  Myelodysplastic syndrome
  Neoplasm
  Neuroblastoma
  Osteosarcoma
  Primitive neuroectodermal tumor
  Retinoblastoma
  Small-cell lung cancer
  Soft tissue sarcoma
  Synovial sarcoma
  Wilms tumor
  Adult lymphoma
  Lymphoma
  Pediatric lymphoma
  Promyelocytic leukaemia
  Small lymphocytic lymphoma
  Microphthalmia, Lenz type
  Childhood myelodysplastic syndrome
  Advanced cancer
  Desmoplastic small round cell tumor
  Malignant rhabdoid tumour
  Neuroepithelial neoplasm
• UniProt ID: BCOR_HUMAN
• PDB ID: 2N1L; 3BIM; 4HPL; 6B7G; 8HCU
• Pfam ID: PF12796 ; PF15808 ; PF16553
• Sequence:
  MLSATPLYGNVHSWMNSERVRMCGASEDRKILVNDGDASKARLELREENPLNHNVVDAST
  AHRIDGLAALSMDRTGLIREGLRVPGNIVYSSLCGLGSEKGREAATSTLGGLGFSSERNP
  EMQFKPNTPETVEASAVSGKPPNGFSAIYKTPPGIQKSAVATAEALGLDRPASDKQSPLN
  INGASYLRLPWVNPYMEGATPAIYPFLDSPNKYSLNMYKALLPQQSYSLAQPLYSPVCTN
  GERFLYLPPPHYVGPHIPSSLASPMRLSTPSASPAIPPLVHCADKSLPWKMGVSPGNPVD
  SHAYPHIQNSKQPRVPSAKAVTSGLPGDTALLLPPSPRPSPRVHLPTQPAADTYSEFHKH
  YARISTSPSVALSKPYMTVSSEFPAARLSNGKYPKAPEGGEGAQPVPGHARKTAVQDRKD
  GSSPPLLEKQTVTKDVTDKPLDLSSKVVDVDASKADHMKKMAPTVLVHSRAGSGLVLSGS
  EIPKETLSPPGNGCAIYRSEIISTAPSSWVVPGPSPNEENNGKSMSLKNKALDWAIPQQR
  SSSCPRMGGTDAVITNVSGSVSSAGRPASASPAPNANADGTKTSRSSVETTPSVIQHVGQ
  PPATPAKHSSSTSSKGAKASNPEPSFKANENGLPPSSIFLSPNEAFRSPPIPYPRSYLPY
  PAPEGIAVSPLSLHGKGPVYPHPVLLPNGSLFPGHLAPKPGLPYGLPTGRPEFVTYQDAL
  GLGMVHPMLIPHTPIEITKEEKPERRSRSHERARYEDPTLRNRFSEILETSSTKLHPDVP
  TDKNLKPNPNWNQGKTVVKSDKLVYVDLLREEPDAKTDTNVSKPSFAAESVGQSAEPPKP
  SVEPALQQHRDFIALREELGRISDFHETYTFKQPVFTVSKDSVLAGTNKENLGLPVSTPF
  LEPPLGSDGPAVTFGKTQEDPKPFCVGSAPPSVDVTPTYTKDGADEAESNDGKVLKPKPS
  KLAKRIANSAGYVGDRFKCVTTELYADSSQLSREQRALQMEGLQEDSILCLPAAYCERAM
  MRFSELEMKEREGGHPATKDSEMCKFSPADWERLKGNQDKKPKSVTLEEAIAEQNESERC
  EYSVGNKHRDPFEAPEDKDLPVEKYFVERQPVSEPPADQVASDMPHSPTLRVDRKRKVSG
  DSSHTETTAEEVPEDPLLKAKRRRVSKDDWPEREMTNSSSNHLEDPHYSELTNLKVCIEL
  TGLHPKKQRHLLHLRERWEQQVSAADGKPGRQSRKEVTQATQPEAIPQGTNITEEKPGRK
  RAEAKGNRSWSEESLKPSDNEQGLPVFSGSPPMKSLSSTSAGGKKQAQPSCAPASRPPAK
  QQKIKENQKTDVLCADEEEDCQAASLLQKYTDNSEKPSGKRLCKTKHLIPQESRRGLPLT
  GEYYVENADGKVTVRRFRKRPEPSSDYDLSPAKQEPKPFDRLQQLLPASQSTQLPCSSSP
  QETTQSRPMPPEARRLIVNKNAGETLLQRAARLGYEEVVLYCLENKICDVNHRDNAGYCA
  LHEACARGWLNIVRHLLEYGADVNCSAQDGTRPLHDAVENDHLEIVRLLLSYGADPTLAT
  YSGRTIMKMTHSELMEKFLTDYLNDLQGRNDDDASGTWDFYGSSVCEPDDESGYDVLANP
  PGPEDQDDDDDAYSDVFEFEFSETPLLPCYNIQVSVAQGPRNWLLLSDVLKKLKMSSRIF
  RCNFPNVEIVTIAEAEFYRQVSASLLFSCSKDLEAFNPESKELLDLVEFTNEIQTLLGSS
  VEWLHPSDLASDNYW
• Function: Transcriptional corepressor. May specifically inhibit gene expression when recruited to promoter regions by sequence-specific DNA-binding proteins such as BCL6 and MLLT3. This repression may be mediated at least in part by histone deacetylase activities which can associate with this corepressor. Involved in the repression of TFAP2A; impairs binding of BCL6 and KDM2B to TFAP2A promoter regions. Via repression of TFAP2A acts as a negative regulator of osteo-dentiogenic capacity in adult stem cells; the function implies inhibition of methylation on histone H3 'Lys-4' (H3K4me3) and 'Lys-36' (H3K36me2).
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway: Polycomb repressive complex (hsa03083)

Molecular Interaction Atlas (MIA) of This DOT

40 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Kidney neoplasm	DISBNZTN	Definitive	Biomarker	[1]
Microphthalmia, syndromic 2	DIS1D0YQ	Definitive	X-linked	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[3]
Autoimmune disease	DISORMTM	Strong	Biomarker	[4]
B-cell neoplasm	DISVY326	Strong	Biomarker	[5]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[6]
Central nervous system neoplasm	DISFC18W	Strong	Biomarker	[7]
Clear cell sarcoma	DIS1MTE6	Strong	Genetic Variation	[8]
Endometrial cancer	DISW0LMR	Strong	Genetic Variation	[9]
Endometrial carcinoma	DISXR5CY	Strong	Genetic Variation	[9]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[10]
Glioma	DIS5RPEH	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[12]
Kidney cancer	DISBIPKM	Strong	Biomarker	[13]
leukaemia	DISS7D1V	Strong	Biomarker	[14]
Leukemia	DISNAKFL	Strong	Biomarker	[15]
Medulloblastoma	DISZD2ZL	Strong	Genetic Variation	[16]
Microphthalmia	DISGEBES	Strong	Genetic Variation	[17]
Microphthalmia, syndromic 1	DISA9P0U	Strong	Genetic Variation	[18]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[19]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[7]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[8]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[20]
Primitive neuroectodermal tumor	DISFHXHA	Strong	Genetic Variation	[11]
Retinoblastoma	DISVPNPB	Strong	Genetic Variation	[12]
Small-cell lung cancer	DISK3LZD	Strong	Genetic Variation	[8]
Soft tissue sarcoma	DISSN8XB	Strong	Genetic Variation	[21]
Synovial sarcoma	DISEZJS7	Strong	Biomarker	[22]
Wilms tumor	DISB6T16	Strong	Biomarker	[23]
Adult lymphoma	DISK8IZR	moderate	Genetic Variation	[24]
Lymphoma	DISN6V4S	moderate	Genetic Variation	[24]
Pediatric lymphoma	DIS51BK2	moderate	Genetic Variation	[24]
Promyelocytic leukaemia	DISYGG13	moderate	FusionGene	[25]
Small lymphocytic lymphoma	DIS30POX	moderate	Biomarker	[26]
Microphthalmia, Lenz type	DISWYX38	Supportive	X-linked	[27]
Childhood myelodysplastic syndrome	DISMN80I	Disputed	Genetic Variation	[19]
Advanced cancer	DISAT1Z9	Limited	Genetic Variation	[15]
Desmoplastic small round cell tumor	DISLI2ME	Limited	Genetic Variation	[8]
Malignant rhabdoid tumour	DIS46HZU	Limited	Genetic Variation	[8]
Neuroepithelial neoplasm	DISCYKLP	Limited	Genetic Variation	[7]

6 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 BCL-6 corepressor (BCOR).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of BCL-6 corepressor (BCOR).	[35]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of BCL-6 corepressor (BCOR).	[37]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of BCL-6 corepressor (BCOR).	[38]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of BCL-6 corepressor (BCOR).	[40]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of BCL-6 corepressor (BCOR).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of BCL-6 corepressor (BCOR).	[29]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of BCL-6 corepressor (BCOR).	[30]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BCL-6 corepressor (BCOR).	[31]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of BCL-6 corepressor (BCOR).	[32]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of BCL-6 corepressor (BCOR).	[33]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of BCL-6 corepressor (BCOR).	[33]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of BCL-6 corepressor (BCOR).	[34]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of BCL-6 corepressor (BCOR).	[36]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of BCL-6 corepressor (BCOR).	[39]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of BCL-6 corepressor (BCOR).	[41]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of BCL-6 corepressor (BCOR).	[42]

References

• [1] Clear Cell Sarcoma of the Kidney.Arch Pathol Lab Med. 2020 Jan;144(1):119-123. doi: 10.5858/arpa.2018-0353-RS. Epub 2019 Mar 27.
• [2] 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.
• [3] Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery.Cancer. 2019 Mar 1;125(5):712-725. doi: 10.1002/cncr.31837. Epub 2018 Nov 27.
• [4] Discovery of a novel B-cell lymphoma 6 (BCL6)-corepressor interaction inhibitor by utilizing structure-based drug design.Bioorg Med Chem. 2017 Sep 1;25(17):4876-4886. doi: 10.1016/j.bmc.2017.07.037. Epub 2017 Jul 20.
• [5] Clear cell sarcoma of kidney involving a horseshoe kidney and harboring EGFR internal tandem duplication.Pediatr Blood Cancer. 2017 Nov;64(11). doi: 10.1002/pbc.26602. Epub 2017 Apr 25.
• [6] IGF1R Is a Potential New Therapeutic Target for HGNET-BCOR Brain Tumor Patients.Int J Mol Sci. 2019 Jun 21;20(12):3027. doi: 10.3390/ijms20123027.
• [7] High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication-a comprehensive clinical, radiographic, pathologic, and genomic analysis.Brain Pathol. 2020 Jan;30(1):46-62. doi: 10.1111/bpa.12747. Epub 2019 Jun 10.
• [8] Review with novel markers facilitates precise categorization of 41 cases of diagnostically challenging, "undifferentiated small round cell tumors". A clinicopathologic, immunophenotypic and molecular analysis.Ann Diagn Pathol. 2018 Jun;34:1-12. doi: 10.1016/j.anndiagpath.2017.11.011. Epub 2017 Nov 29.
• [9] Chromatin remodelling and DNA repair genes are frequently mutated in endometrioid endometrial carcinoma.Int J Cancer. 2017 Apr 1;140(7):1551-1563. doi: 10.1002/ijc.30573. Epub 2017 Feb 2.
• [10] Fine-Needle Aspiration Features of BCOR-CCNB3 Sarcoma.Am J Clin Pathol. 2020 Feb 8;153(3):315-321. doi: 10.1093/ajcp/aqz159.
• [11] CNS high-grade neuroepithelial tumor with BCOR internal tandem duplication: a comparison with its counterparts in the kidney and soft tissue.Brain Pathol. 2018 Sep;28(5):710-720. doi: 10.1111/bpa.12585. Epub 2017 Dec 28.
• [12] Clarifying the impact of polycomb complex component disruption in human cancers.Mol Cancer Res. 2014 Apr;12(4):479-84. doi: 10.1158/1541-7786.MCR-13-0596. Epub 2014 Feb 10.
• [13] Consistent in-frame internal tandem duplications of BCOR characterize clear cell sarcoma of the kidney.Nat Genet. 2015 Aug;47(8):861-3. doi: 10.1038/ng.3338. Epub 2015 Jun 22.
• [14] Cytogenetic and molecular profile of endometrial stromal sarcoma.Genes Chromosomes Cancer. 2016 Nov;55(11):834-46. doi: 10.1002/gcc.22380. Epub 2016 Aug 9.
• [15] Bcor loss perturbs myeloid differentiation and promotes leukaemogenesis.Nat Commun. 2019 Mar 22;10(1):1347. doi: 10.1038/s41467-019-09250-6.
• [16] Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy.Neuro Oncol. 2017 May 1;19(5):699-709. doi: 10.1093/neuonc/now254.
• [17] Congenital cataracts in females caused by BCOR mutations; report of six further families demonstrating clinical variability and diverse genetic mechanisms.Eur J Med Genet. 2020 Feb;63(2):103658. doi: 10.1016/j.ejmg.2019.04.015. Epub 2019 Apr 30.
• [18] Microphthalmia is not a mandatory finding in X-linked recessive syndromic microphthalmia caused by the recurrent BCOR variant p.Pro85Leu.Am J Med Genet A. 2018 Dec;176(12):2872-2876. doi: 10.1002/ajmg.a.40640. Epub 2018 Nov 18.
• [19] Concurrent mutations in other epigenetic modulators portend better prognosis in BCOR-mutated myelodysplastic syndrome.J Clin Pathol. 2020 Apr;73(4):209-212. doi: 10.1136/jclinpath-2019-206132. Epub 2019 Nov 26.
• [20] BCOR-CCNB3 (Ewing-like) sarcoma: a clinicopathologic analysis of 10 cases, in comparison with conventional Ewing sarcoma.Am J Surg Pathol. 2014 Oct;38(10):1307-18. doi: 10.1097/PAS.0000000000000223.
• [21] DNA methylation profiling distinguishes Ewing-like sarcoma with EWSR1-NFATc2 fusion from Ewing sarcoma.J Cancer Res Clin Oncol. 2019 May;145(5):1273-1281. doi: 10.1007/s00432-019-02895-2. Epub 2019 Mar 20.
• [22] New fusion sarcomas: histopathology and clinical significance of selected entities.Hum Pathol. 2019 Apr;86:57-65. doi: 10.1016/j.humpath.2018.12.006. Epub 2019 Jan 8.
• [23] A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor.Nat Genet. 2017 Oct;49(10):1487-1494. doi: 10.1038/ng.3940. Epub 2017 Aug 21.
• [24] Exome sequencing identifies recurrent BCOR alterations and the absence of KLF2, TNFAIP3 and MYD88 mutations in splenic diffuse red pulp small B-cell lymphoma.Haematologica. 2017 Oct;102(10):1758-1766. doi: 10.3324/haematol.2016.160192. Epub 2017 Jul 27.
• [25] Successful treatment of acute promyelocytic leukemia with a t(X;17)(p11.4;q21) and BCOR-RARA fusion gene.Cancer Genet. 2015 Apr;208(4):162-3. doi: 10.1016/j.cancergen.2015.01.008. Epub 2015 Feb 2.
• [26] Bcl6a function is required during optic cup formation to prevent p53-dependent apoptosis and colobomata.Hum Mol Genet. 2013 Sep 1;22(17):3568-82. doi: 10.1093/hmg/ddt211. Epub 2013 May 12.
• [27] Lenz Microphthalmia Syndrome C RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2002 Jun 4 [updated 2014 Oct 2]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [28] 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.
• [29] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [30] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [31] 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.
• [32] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [33] 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.
• [34] Gene-expression profiling during curcumin-induced apoptosis reveals downregulation of CXCR4. Exp Hematol. 2007 Jan;35(1):84-95.
• [35] 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.
• [36] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [37] 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.
• [38] 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.
• [39] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [40] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [41] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [42] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.