Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTV0V70M)

• DOT Name: Ankyrin repeat domain-containing protein 11 (ANKRD11)
• Synonyms: Ankyrin repeat-containing cofactor 1
• Gene Name: ANKRD11
• Related Disease:
  KBG syndrome
  Melanoma
  Advanced cancer
  Autism
  Autism spectrum disorder
  Epilepsy
  Epithelial ovarian cancer
  Intellectual disability
  Kabuki syndrome
  Metabolic bone disease
  Neurodevelopmental disorder
  Ovarian cancer
  Ovarian neoplasm
  Breast cancer
  Breast carcinoma
  Neoplasm
  Congenital heart defects, multiple types
  Squamous cell carcinoma
• UniProt ID: ANR11_HUMAN
• Pfam ID: PF12796
• Sequence:
  MPKGGCPKAPQQEELPLSSDMVEKQTGKKDKDKVSLTKTPKLERGDGGKEVRERASKRKL
  PFTAGANGEQKDSDTEKQGPERKRIKKEPVTRKAGLLFGMGLSGIRAGYPLSERQQVALL
  MQMTAEESANSPVDTTPKHPSQSTVCQKGTPNSASKTKDKVNKRNERGETRLHRAAIRGD
  ARRIKELISEGADVNVKDFAGWTALHEACNRGYYDVAKQLLAAGAEVNTKGLDDDTPLHD
  AANNGHYKVVKLLLRYGGNPQQSNRKGETPLKVANSPTMVNLLLGKGTYTSSEESSTESS
  EEEDAPSFAPSSSVDGNNTDSEFEKGLKHKAKNPEPQKATAPVKDEYEFDEDDEQDRVPP
  VDDKHLLKKDYRKETKSNSFISIPKMEVKSYTKNNTIAPKKASHRILSDTSDEEDASVTV
  GTGEKLRLSAHTILPGSKTREPSNAKQQKEKNKVKKKRKKETKGREVRFGKRSDKFCSSE
  SESESSESGEDDRDSLGSSGCLKGSPLVLKDPSLFSSLSASSTSSHGSSAAQKQNPSHTD
  QHTKHWRTDNWKTISSPAWSEVSSLSDSTRTRLTSESDYSSEGSSVESLKPVRKRQEHRK
  RASLSEKKSPFLSSAEGAVPKLDKEGKVVKKHKTKHKHKNKEKGQCSISQELKLKSFTYE
  YEDSKQKSDKAILLENDLSTENKLKVLKHDRDHFKKEEKLSKMKLEEKEWLFKDEKSLKR
  IKDTNKDISRSFREEKDRSNKAEKERSLKEKSPKEEKLRLYKEERKKKSKDRPSKLEKKN
  DLKEDKISKEKEKIFKEDKEKLKKEKVYREDSAFDEYCNKNQFLENEDTKFSLSDDQRDR
  WFSDLSDSSFDFKGEDSWDSPVTDYRDMKSDSVAKLILETVKEDSKERRRDSRAREKRDY
  REPFFRKKDRDYLDKNSEKRKEQTEKHKSVPGYLSEKDKKRRESAEAGRDRKDALESCKE
  RRDGRAKPEEAHREELKECGCESGFKDKSDGDFGKGLEPWERHHPAREKEKKDGPDKERK
  EKTKPERYKEKSSDKDKSEKSILEKCQKDKEFDKCFKEKKDTKEKHKDTHGKDKERKASL
  DQGKEKKEKAFPGIISEDFSEKKDDKKGKEKSWYIADIFTDESEDDRDSCMGSGFKMGEA
  SDLPRTDGLQEKEEGREAYASDRHRKSSDKQHPERQKDKEPRDRRKDRGAADAGRDKKEK
  VFEKHKEKKDKESTEKYKDRKDRASVDSTQDKKNKQKLPEKAEKKHAAEDKAKSKHKEKS
  DKEHSKERKSSRSADAEKSLLEKLEEEALHEYREDSNDKISEVSSDSFTDRGQEPGLTAF
  LEVSFTEPPGDDKPRESACLPEKLKEKERHRHSSSSSKKSHDRERAKKEKAEKKEKGEDY
  KEGGSRKDSGQYEKDFLEADAYGVSYNMKADIEDELDKTIELFSTEKKDKNDSEREPSKK
  IEKELKPYGSSAINILKEKKKREKHREKWRDEKERHRDRHADGLLRHHRDELLRHHRDEQ
  KPATRDKDSPPRVLKDKSRDEGPRLGDAKLKEKFKDGAEKEKGDPVKMSNGNDKVAPSKD
  PGKKDARPREKLLGDGDLMMTSFERMLSQKDLEIEERHKRHKERMKQMEKLRHRSGDPKL
  KEKAKPADDGRKKGLDIPAKKPPGLDPPFKDKKLKESTPIPPAAENKLHPASGADSKDWL
  AGPHMKEVLPASPRPDQSRPTGVPTPTSVLSCPSYEEVMHTPRTPSCSADDYADLVFDCA
  DSQHSTPVPTAPTSACSPSFFDRFSVASSGLSENASQAPARPLSTNLYRSVSVDIRRTPE
  EEFSVGDKLFRQQSVPAASSYDSPMPPSMEDRAPLPPVPAEKFACLSPGYYSPDYGLPSP
  KVDALHCPPAAVVTVTPSPEGVFSSLQAKPSPSPRAELLVPSLEGALPPDLDTSEDQQAT
  AAIIPPEPSYLEPLDEGPFSAVITEEPVEWAHPSEQALASSLIGGTSENPVSWPVGSDLL
  LKSPQRFPESPKRFCPADPLHSAAPGPFSASEAPYPAPPASPAPYALPVAEPGLEDVKDG
  VDAVPAAISTSEAAPYAPPSGLESFFSNCKSLPEAPLDVAPEPACVAAVAQVEALGPLEN
  SFLDGSRGLSHLGQVEPVPWADAFAGPEDDLDLGPFSLPELPLQTKDAADGEAEPVEESL
  APPEEMPPGAPGVINGGDVSTVVAEEPPALPPDQASTRLPAELEPEPSGEPKLDVALEAA
  VEAETVPEERARGDPDSSVEPAPVPPEQRPLGSGDQGAEAEGPPAASLCAPDGPAPNTVA
  QAQAADGAGPEDDTEASRAAAPAEGPPGGIQPEAAEPKPTAEAPKAPRVEEIPQRMTRNR
  AQMLANQSKQGPPPSEKECAPTPAPVTRAKARGSEDDDAQAQHPRKRRFQRSTQQLQQQL
  NTSTQQTREVIQQTLAAIVDAIKLDAIEPYHSDRANPYFEYLQIRKKIEEKRKILCCITP
  QAPQCYAEYVTYTGSYLLDGKPLSKLHIPVIAPPPSLAEPLKELFRQQEAVRGKLRLQHS
  IEREKLIVSCEQEILRVHCRAARTIANQAVPFSACTMLLDSEVYNMPLESQGDENKSVRD
  RFNARQFISWLQDVDDKYDRMKTCLLMRQQHEAAALNAVQRMEWQLKVQELDPAGHKSLC
  VNEVPSFYVPMVDVNDDFVLLPA
• Function: Chromatin regulator which modulates histone acetylation and gene expression in neural precursor cells. May recruit histone deacetylases (HDACs) to the p160 coactivators/nuclear receptor complex to inhibit ligand-dependent transactivation. Has a role in proliferation and development of cortical neural precursors. May also regulate bone homeostasis.

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
KBG syndrome	DISUXA2M	Definitive	Autosomal dominant	[1]
Melanoma	DIS1RRCY	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Autism	DISV4V1Z	Strong	Biomarker	[4]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[5]
Epilepsy	DISBB28L	Strong	Biomarker	[6]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[7]
Intellectual disability	DISMBNXP	Strong	Biomarker	[4]
Kabuki syndrome	DISZN97H	Strong	Genetic Variation	[8]
Metabolic bone disease	DISO7RI8	Strong	Biomarker	[9]
Neurodevelopmental disorder	DIS372XH	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[7]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[7]
Breast cancer	DIS7DPX1	moderate	Biomarker	[10]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[10]
Neoplasm	DISZKGEW	moderate	Biomarker	[11]
Congenital heart defects, multiple types	DISWZRYW	Limited	Autosomal dominant	[12]
Squamous cell carcinoma	DISQVIFL	Limited	Genetic Variation	[13]

5 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 Ankyrin repeat domain-containing protein 11 (ANKRD11).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[30]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[21]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[22]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[23]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[25]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[26]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[27]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[29]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Ankyrin repeat domain-containing protein 11 (ANKRD11).	[31]

References

• [1] 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.
• [2] A unique genome-wide association analysis in extended Utah high-risk pedigrees identifies a novel melanoma risk variant on chromosome arm 10q.Hum Genet. 2012 Jan;131(1):77-85. doi: 10.1007/s00439-011-1048-z. Epub 2011 Jun 26.
• [3] KBG syndrome patient due to 16q24.3 microdeletion presenting with a paratesticular rhabdoid tumor: Coincidence or cancer predisposition?.Am J Med Genet A. 2018 Jun;176(6):1449-1454. doi: 10.1002/ajmg.a.38724. Epub 2018 Apr 25.
• [4] ANKRD11 associated with intellectual disability and autism regulates dendrite differentiation via the BDNF/TrkB signaling pathway.Neurobiol Dis. 2018 Mar;111:138-152. doi: 10.1016/j.nbd.2017.12.008. Epub 2017 Dec 21.
• [5] Partial deletion of ANKRD11 results in the KBG phenotype distinct from the 16q24.3 microdeletion syndrome.Am J Med Genet A. 2013 Apr;161A(4):835-40. doi: 10.1002/ajmg.a.35739. Epub 2013 Mar 12.
• [6] De novo variants in neurodevelopmental disorders with epilepsy.Nat Genet. 2018 Jul;50(7):1048-1053. doi: 10.1038/s41588-018-0143-7. Epub 2018 Jun 25.
• [7] Whole-exome sequencing of ovarian cancer families uncovers putative predisposition genes.Int J Cancer. 2020 Apr 15;146(8):2147-2155. doi: 10.1002/ijc.32545. Epub 2019 Jul 16.
• [8] De novo ANKRD11 and KDM1A gene mutations in a male with features of KBG syndrome and Kabuki syndrome. Am J Med Genet A. 2014 Jul;164A(7):1744-9. doi: 10.1002/ajmg.a.36450. Epub 2014 May 16.
• [9] An ENU-induced mutation in the Ankrd11 gene results in an osteopenia-like phenotype in the mouse mutant Yoda. Physiol Genomics. 2008 Feb 19;32(3):311-21. doi: 10.1152/physiolgenomics.00116.2007. Epub 2007 Nov 6.
• [10] Loss of ANCO1 repression at AIB1/YAP targets drives breast cancer progression.EMBO Rep. 2020 Jan 7;21(1):e48741. doi: 10.15252/embr.201948741. Epub 2019 Dec 2.
• [11] One repressor to rule them all: ANCO1 links YAP and AIB1.EMBO Rep. 2020 Jan 7;21(1):e49647. doi: 10.15252/embr.201949647. Epub 2019 Dec 2.
• [12] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [13] Combined analysis of keratinocyte cancers identifies novel genome-wide loci.Hum Mol Genet. 2019 Sep 15;28(18):3148-3160. doi: 10.1093/hmg/ddz121.
• [14] 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.
• [15] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [19] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [20] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [21] 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.
• [22] 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.
• [23] Pharmacogenomic identification of novel determinants of response to chemotherapy in colon cancer. Cancer Res. 2006 Mar 1;66(5):2765-77.
• [24] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [27] 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.
• [28] 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.
• [29] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [30] 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.
• [31] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.