Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPTFQN5)

• DOT Name: BCL-6 corepressor-like protein 1 (BCORL1)
• Synonyms: BCoR-L1; BCoR-like protein 1
• Gene Name: BCORL1
• Related Disease:
  Aplastic anemia
  Autoimmune disease
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Hepatocellular carcinoma
  Intellectual disability
  leukaemia
  Leukemia
  Myelodysplastic syndrome
  Neoplasm
  Promyelocytic leukaemia
  Retinoblastoma
  Shukla-Vernon syndrome
  Wilms tumor
  Syndromic intellectual disability
  Dental caries
  Metastatic malignant neoplasm
  Myeloid neoplasm
• UniProt ID: BCORL_HUMAN
• PDB ID: 4HPM; 5JH5
• Pfam ID: PF12796 ; PF16553
• Sequence:
  MISTAPLYSGVHNWTSSDRIRMCGINEERRAPLSDEESTTGDCQHFGSQEFCVSSSFSKV
  ELTAVGSGSNARGADPDGSATEKLGHKSEDKPDDPQPKMDYAGNVAEAEGLLVPLSSPGD
  GLKLPASDSAEASNSRADCSWTPLNTQMSKQVDCSPAGVKALDSRQGVGEKNTFILATLG
  TGVPVEGTLPLVTTNFSPLPAPICPPAPGSASVPHSVPDAFQVPLSVPAPVPHSGLVPVQ
  VATSVPAPSPPLAPVPALAPAPPSVPTLISDSNPLSVSASVLVPVPASAPPSGPVPLSAP
  APAPLSVPVSAPPLALIQAPVPPSAPTLVLAPVPTPVLAPMPASTPPAAPAPPSVPMPTP
  TPSSGPPSTPTLIPAFAPTPVPAPTPAPIFTPAPTPMPAATPAAIPTSAPIPASFSLSRV
  CFPAAQAPAMQKVPLSFQPGTVLTPSQPLVYIPPPSCGQPLSVATLPTTLGVSSTLTLPV
  LPSYLQDRCLPGVLASPELRSYPYAFSVARPLTSDSKLVSLEVNRLPCTSPSGSTTTQPA
  PDGVPGPLADTSLVTASAKVLPTPQPLLPAPSGSSAPPHPAKMPSGTEQQTEGTSVTFSP
  LKSPPQLEREMASPPECSEMPLDLSSKSNRQKLPLPNQRKTPPMPVLTPVHTSSKALLST
  VLSRSQRTTQAAGGNVTSCLGSTSSPFVIFPEIVRNGDPSTWVKNSTALISTIPGTYVGV
  ANPVPASLLLNKDPNLGLNRDPRHLPKQEPISIIDQGEPKGTGATCGKKGSQAGAEGQPS
  TVKRYTPARIAPGLPGCQTKELSLWKPTGPANIYPRCSVNGKPTSTQVLPVGWSPYHQAS
  LLSIGISSAGQLTPSQGAPIRPTSVVSEFSGVPSLSSSEAVHGLPEGQPRPGGSFVPEQD
  PVTKNKTCRIAAKPYEEQVNPVLLTLSPQTGTLALSVQPSGGDIRMNQGPEESESHLCSD
  STPKMEGPQGACGLKLAGDTKPKNQVLATYMSHELVLATPQNLPKMPELPLLPHDSHPKE
  LILDVVPSSRRGSSTERPQLGSQVDLGRVKMEKVDGDVVFNLATCFRADGLPVAPQRGQA
  EVRAKAGQARVKQESVGVFACKNKWQPDDVTESLPPKKMKCGKEKDSEEQQLQPQAKAVV
  RSSHRPKCRKLPSDPQESTKKSPRGASDSGKEHNGVRGKHKHRKPTKPESQSPGKRADSH
  EEGSLEKKAKSSFRDFIPVVLSTRTRSQSGSICSSFAGMADSDMGSQEVFPTEEEEEVTP
  TPAKRRKVRKTQRDTQYRSHHAQDKSLLSQGRRHLWRAREMPWRTEAARQMWDTNEEEEE
  EEEEGLLKRKKRRRQKSRKYQTGEYLTEQEDEQRRKGRADLKARKQKTSSSQSLEHRLRN
  RNLLLPNKVQGISDSPNGFLPNNLEEPACLENSEKPSGKRKCKTKHMATVSEEAKGKGRW
  SQQKTRSPKSPTPVKPTEPCTPSKSRSASSEEASESPTARQIPPEARRLIVNKNAGETLL
  QRAARLGYKDVVLYCLQKDSEDVNHRDNAGYTALHEACSRGWTDILNILLEHGANVNCSA
  QDGTRPVHDAVVNDNLETIWLLLSYGADPTLATYSGQTAMKLASSDTMKRFLSDHLSDLQ
  GRAEGDPGVSWDFYSSSVLEEKDGFACDLLHNPPGSSDQEGDDPMEEDDFMFELSDKPLL
  PCYNLQVSVSRGPCNWFLFSDVLKRLKLSSRIFQARFPHFEITTMPKAEFYRQVASSQLL
  TPAERPGGLDDRSPPGSSETVELVRYEPDLLRLLGSEVEFQSCNS
• Function: Transcriptional corepressor. May specifically inhibit gene expression when recruited to promoter regions by sequence-specific DNA-binding proteins such as BCL6. This repression may be mediated at least in part by histone deacetylase activities which can associate with this corepressor.
• Tissue Specificity: Detected in testis and prostate. Detected at lower levels in peripheral blood leukocytes and spleen.
• KEGG Pathway: Polycomb repressive complex (hsa03083)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Aplastic anemia	DISJRSC0	Definitive	Genetic Variation	[1]
Autoimmune disease	DISORMTM	Definitive	Genetic Variation	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Genetic Variation	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[6]
leukaemia	DISS7D1V	Strong	Biomarker	[7]
Leukemia	DISNAKFL	Strong	Biomarker	[7]
Myelodysplastic syndrome	DISYHNUI	Strong	Genetic Variation	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[8]
Retinoblastoma	DISVPNPB	Strong	Genetic Variation	[8]
Shukla-Vernon syndrome	DIS0F3KX	Strong	X-linked	[6]
Wilms tumor	DISB6T16	Strong	Biomarker	[9]
Syndromic intellectual disability	DISH7SDF	Supportive	Autosomal dominant	[6]
Dental caries	DISRBCMD	Limited	Biomarker	[10]
Metastatic malignant neoplasm	DIS86UK6	Limited	Biomarker	[5]
Myeloid neoplasm	DIS2YOWO	Limited	Genetic Variation	[3]

4 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-like protein 1 (BCORL1).	[11]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of BCL-6 corepressor-like protein 1 (BCORL1).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of BCL-6 corepressor-like protein 1 (BCORL1).	[25]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of BCL-6 corepressor-like protein 1 (BCORL1).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of BCL-6 corepressor-like protein 1 (BCORL1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of BCL-6 corepressor-like protein 1 (BCORL1).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of BCL-6 corepressor-like protein 1 (BCORL1).	[14]
Marinol	DM70IK5	Approved	Marinol increases the expression of BCL-6 corepressor-like protein 1 (BCORL1).	[15]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of BCL-6 corepressor-like protein 1 (BCORL1).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of BCL-6 corepressor-like protein 1 (BCORL1).	[17]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of BCL-6 corepressor-like protein 1 (BCORL1).	[18]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of BCL-6 corepressor-like protein 1 (BCORL1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of BCL-6 corepressor-like protein 1 (BCORL1).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of BCL-6 corepressor-like protein 1 (BCORL1).	[21]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of BCL-6 corepressor-like protein 1 (BCORL1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of BCL-6 corepressor-like protein 1 (BCORL1).	[24]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of BCL-6 corepressor-like protein 1 (BCORL1).	[26]

References

• [1] Clonal hematopoiesis in acquired aplastic anemia.Blood. 2016 Jul 21;128(3):337-47. doi: 10.1182/blood-2016-01-636381. Epub 2016 Apr 27.
• [2] ASXL2 mutations are frequently found in pediatric AML patients with t(8;21)/ RUNX1-RUNX1T1 and associated with a better prognosis.Genes Chromosomes Cancer. 2017 May;56(5):382-393. doi: 10.1002/gcc.22443. Epub 2017 Feb 14.
• [3] C-terminal RUNX1 mutation in familial platelet disorder with predisposition to myeloid malignancies.Int J Hematol. 2018 Dec;108(6):652-657. doi: 10.1007/s12185-018-2514-3. Epub 2018 Aug 6.
• [4] BCoR-L1 variation and breast cancer.Breast Cancer Res. 2007;9(4):R54. doi: 10.1186/bcr1759.
• [5] MicroRNA-876-5p inhibits epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma by targeting BCL6 corepressor like 1.Biomed Pharmacother. 2018 Jul;103:645-652. doi: 10.1016/j.biopha.2018.04.037. Epub 2018 Apr 24.
• [6] Variants in the transcriptional corepressor BCORL1 are associated with an X-linked disorder of intellectual disability, dysmorphic features, and behavioral abnormalities. Am J Med Genet A. 2019 May;179(5):870-874. doi: 10.1002/ajmg.a.61118. Epub 2019 Apr 2.
• [7] Tumor SHB gene expression affects disease characteristics in human acute myeloid leukemia.Tumour Biol. 2017 Oct;39(10):1010428317720643. doi: 10.1177/1010428317720643.
• [8] 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.
• [9] 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.
• [10] Genome-wide association studies of pit-and-fissure- and smooth-surface caries in permanent dentition.J Dent Res. 2013 May;92(5):432-7. doi: 10.1177/0022034513481976. Epub 2013 Mar 7.
• [11] 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.
• [12] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [16] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [17] Cannabidiol Activates Neuronal Precursor Genes in Human Gingival Mesenchymal Stromal Cells. J Cell Biochem. 2017 Jun;118(6):1531-1546. doi: 10.1002/jcb.25815. Epub 2016 Dec 29.
• [18] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [21] 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.
• [22] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [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] 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.
• [25] 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.
• [26] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.