Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2YY35L)

• DOT Name: Anaphase-promoting complex subunit 1 (ANAPC1)
• Synonyms: APC1; Cyclosome subunit 1; Mitotic checkpoint regulator; Testis-specific gene 24 protein
• Gene Name: ANAPC1
• Related Disease:
  Alcohol dependence
  Colonic neoplasm
  Familial adenomatous polyposis
  Gastric cancer
  Hepatocellular carcinoma
  Rothmund-Thomson syndrome type 1
  Stomach cancer
  Keratoconus
  Nicotine dependence
  Colorectal carcinoma
  Glaucoma/ocular hypertension
• UniProt ID: APC1_HUMAN
• PDB ID: 4UI9; 5A31; 5G04; 5G05; 5KHR; 5KHU; 5L9T; 5L9U; 5LCW; 5LGG; 6Q6G; 6Q6H; 6TLJ; 6TM5; 6TNT; 7QE7; 8PKP; 8TAR; 8TAU
• Pfam ID: PF12859 ; PF21282 ; PF18122 ; PF20518
• Sequence:
  MSNFYEERTTMIAARDLQEFVPFGRDHCKHHPNALNLQLRQLQPASELWSSDGAAGLVGS
  LQEVTIHEKQKESWQLRKGVSEIGEDVDYDEELYVAGNMVIWSKGSKSQALAVYKAFTVD
  SPVQQALWCDFIISQDKSEKAYSSNEVEKCICILQSSCINMHSIEGKDYIASLPFQVANV
  WPTKYGLLFERSASSHEVPPGSPREPLPTMFSMLHPLDEITPLVCKSGSLFGSSRVQYVV
  DHAMKIVFLNTDPSIVMTYDAVQNVHSVWTLRRVKSEEENVVLKFSEQGGTPQNVATSSS
  LTAHLRSLSKGDSPVTSPFQNYSSIHSQSRSTSSPSLHSRSPSISNMAALSRAHSPALGV
  HSFSGVQRFNISSHNQSPKRHSISHSPNSNSNGSFLAPETEPIVPELCIDHLWTETITNI
  REKNSQASKVFITSDLCGQKFLCFLVESQLQLRCVKFQESNDKTQLIFGSVTNIPAKDAA
  PVEKIDTMLVLEGSGNLVLYTGVVRVGKVFIPGLPAPSLTMSNTMPRPSTPLDGVSTPKP
  LSKLLGSLDEVVLLSPVPELRDSSKLHDSLYNEDCTFQQLGTYIHSIRDPVHNRVTLELS
  NGSMVRITIPEIATSELVQTCLQAIKFILPKEIAVQMLVKWYNVHSAPGGPSYHSEWNLF
  VTCLMNMMGYNTDRLAWTRNFDFEGSLSPVIAPKKARPSETGSDDDWEYLLNSDYHQNVE
  SHLLNRSLCLSPSEASQMKDEDFSQNLSLDSSTLLFTHIPAIFFVLHLVYEELKLNTLMG
  EGICSLVELLVQLARDLKLGPYVDHYYRDYPTLVRTTGQVCTIDPGQTGFMHHPSFFTSE
  PPSIYQWVSSCLKGEGMPPYPYLPGICERSRLVVLSIALYILGDESLVSDESSQYLTRIT
  IAPQKLQVEQEENRFSFRHSTSVSSLAERLVVWMTNVGFTLRDLETLPFGIALPIRDAIY
  HCREQPASDWPEAVCLLIGRQDLSKQACEGNLPKGKSVLSSDVPSGTETEEEDDGMNDMN
  HEVMSLIWSEDLRVQDVRRLLQSAHPVRVNVVQYPELSDHEFIEEKENRLLQLCQRTMAL
  PVGRGMFTLFSYHPVPTEPLPIPKLNLTGRAPPRNTTVDLNSGNIDVPPNMTSWASFHNG
  VAAGLKIAPASQIDSAWIVYNKPKHAELANEYAGFLMALGLNGHLTKLATLNIHDYLTKG
  HEMTSIGLLLGVSAAKLGTMDMSITRLLSIHIPALLPPTSTELDVPHNVQVAAVVGIGLV
  YQGTAHRHTAEVLLAEIGRPPGPEMEYCTDRESYSLAAGLALGMVCLGHGSNLIGMSDLN
  VPEQLYQYMVGGHRRFQTGMHREKHKSPSYQIKEGDTINVDVTCPGATLALAMIYLKTNN
  RSIADWLRAPDTMYLLDFVKPEFLLLRTLARCLILWDDILPNSKWVDSNVPQIIRENSIS
  LSEIELPCSEDLNLETLSQAHVYIIAGACLSLGFRFAGSENLSAFNCLHKFAKDFMTYLS
  APNASVTGPHNLETCLSVVLLSLAMVMAGSGNLKVLQLCRFLHMKTGGEMNYGFHLAHHM
  ALGLLFLGGGRYSLSTSNSSIAALLCALYPHFPAHSTDNRYHLQALRHLYVLAAEPRLLV
  PVDVDTNTPCYALLEVTYKGTQWYEQTKEELMAPTLLPELHLLKQIKVKGPRYWELLIDL
  SKGTQHLKSILSKDGVLYVKLRAGQLSYKEDPMGWQSLLAQTVANRNSEARAFKPETISA
  FTSDPALLSFAEYFCKPTVNMGQKQEILDLFSSVLYECVTQETPEMLPAYIAMDQAIRRL
  GRREMSETSELWQIKLVLEFFSSRSHQERLQNHPKRGLFMNSEFLPVVKCTIDNTLDQWL
  QVGGDMCVHAYLSGQPLEESQLSMLACFLVYHSVPAPQHLPPIGLEGSTSFAELLFKFKQ
  LKMPVRALLRLAPLLLGNPQPMVM
• Function: Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.
• KEGG Pathway:
  Cell cycle (hsa04110)
  Oocyte meiosis (hsa04114)
  Ubiquitin mediated proteolysis (hsa04120)
  Progesterone-mediated oocyte maturation (hsa04914)
  Human T-cell leukemia virus 1 infection (hsa05166)
• Reactome Pathway:
  APC/C (R-HSA-174048)
  Autodegradation of Cdh1 by Cdh1 (R-HSA-174084)
  APC/C (R-HSA-174154)
  APC/C (R-HSA-174178)
  Cdc20 (R-HSA-174184)
  Conversion from APC/C (R-HSA-176407)
  Regulation of APC/C activators between G1/S and early anaphase (R-HSA-176408)
  APC/C (R-HSA-176409)
  Phosphorylation of the APC/C (R-HSA-176412)
  APC-Cdc20 mediated degradation of Nek2A (R-HSA-179409)
  Separation of Sister Chromatids (R-HSA-2467813)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  Assembly of the pre-replicative complex (R-HSA-68867)
  CDK-mediated phosphorylation and removal of Cdc6 (R-HSA-69017)
  Transcriptional Regulation by VENTX (R-HSA-8853884)
  Aberrant regulation of mitotic exit in cancer due to RB1 defects (R-HSA-9687136)
  Antigen processing (R-HSA-983168)
  Inactivation of APC/C via direct inhibition of the APC/C complex (R-HSA-141430)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alcohol dependence	DIS4ZSCO	Strong	Biomarker	[1]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[2]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Posttranslational Modification	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Rothmund-Thomson syndrome type 1	DISDL42Q	Strong	Autosomal recessive	[6]
Stomach cancer	DISKIJSX	Strong	Posttranslational Modification	[4]
Keratoconus	DISOONXH	moderate	Genetic Variation	[7]
Nicotine dependence	DISZD9W7	moderate	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[8]
Glaucoma/ocular hypertension	DISLBXBY	Limited	Biomarker	[9]

14 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 Anaphase-promoting complex subunit 1 (ANAPC1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Anaphase-promoting complex subunit 1 (ANAPC1).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Anaphase-promoting complex subunit 1 (ANAPC1).	[12]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Anaphase-promoting complex subunit 1 (ANAPC1).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Anaphase-promoting complex subunit 1 (ANAPC1).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Anaphase-promoting complex subunit 1 (ANAPC1).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Anaphase-promoting complex subunit 1 (ANAPC1).	[16]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Anaphase-promoting complex subunit 1 (ANAPC1).	[17]
Gemcitabine	DMSE3I7	Approved	Gemcitabine increases the expression of Anaphase-promoting complex subunit 1 (ANAPC1).	[18]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Anaphase-promoting complex subunit 1 (ANAPC1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Anaphase-promoting complex subunit 1 (ANAPC1).	[20]
Scriptaid	DM9JZ21	Preclinical	Scriptaid affects the expression of Anaphase-promoting complex subunit 1 (ANAPC1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Anaphase-promoting complex subunit 1 (ANAPC1).	[19]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Anaphase-promoting complex subunit 1 (ANAPC1).	[23]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Anaphase-promoting complex subunit 1 (ANAPC1).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Anaphase-promoting complex subunit 1 (ANAPC1).	[21]

References

• [1] ANAPC1 and SLCO3A1 are associated with nicotine dependence: meta-analysis of genome-wide association studies.Drug Alcohol Depend. 2012 Aug 1;124(3):325-32. doi: 10.1016/j.drugalcdep.2012.02.003. Epub 2012 Feb 28.
• [2] Regulation of Skp2-p27 axis by the Cdh1/anaphase-promoting complex pathway in colorectal tumorigenesis.Am J Pathol. 2008 Jul;173(1):217-28. doi: 10.2353/ajpath.2008.070957. Epub 2008 Jun 5.
• [3] APC-activated long noncoding RNA inhibits colorectal carcinoma pathogenesis through reduction of exosome production.J Clin Invest. 2019 Feb 1;129(2):727-743. doi: 10.1172/JCI122478. Epub 2019 Jan 14.
• [4] Methylation status of ANAPC1, CDKN2A and TP53 promoter genes in individuals with gastric cancer.Braz J Med Biol Res. 2008 Jun;41(6):539-43. doi: 10.1590/s0100-879x2008000600017.
• [5] Mutation analysis of p31comet gene, a negative regulator of Mad2, in human hepatocellular carcinoma.Exp Mol Med. 2007 Aug 31;39(4):508-13. doi: 10.1038/emm.2007.56.
• [6] Adult neuropsychiatric expression and familial segregation of 2q13 duplications. Am J Med Genet B Neuropsychiatr Genet. 2014 Jun;165B(4):337-44. doi: 10.1002/ajmg.b.32236. Epub 2014 May 8.
• [7] Genetic Variants Associated With Corneal Biomechanical Properties and Potentially Conferring Susceptibility to Keratoconus in a Genome-Wide Association Study.JAMA Ophthalmol. 2019 Sep 1;137(9):1005-1012. doi: 10.1001/jamaophthalmol.2019.2058.
• [8] Selection and characterization of novel DNA aptamer against colorectal carcinoma Caco-2 cells.Biotechnol Appl Biochem. 2019 May;66(3):412-418. doi: 10.1002/bab.1737. Epub 2019 Feb 21.
• [9] Sequence variation at ANAPC1 accounts for 24% of the variability in corneal endothelial cell density.Nat Commun. 2019 Mar 20;10(1):1284. doi: 10.1038/s41467-019-09304-9.
• [10] A comparative transcriptomic study on the effects of valproic acid on two different hESCs lines in a neural teratogenicity test system. Toxicol Lett. 2014 Nov 18;231(1):38-44.
• [11] 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.
• [12] 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.
• [13] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [14] 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.
• [15] 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.
• [16] Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ Toxicol. 2018 Nov;33(11):1168-1181. doi: 10.1002/tox.22623. Epub 2018 Aug 27.
• [17] 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.
• [18] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [19] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [20] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [21] 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.
• [22] Histone deacetylase inhibitor scriptaid induces cell cycle arrest and epigenetic change in colon cancer cells. Int J Oncol. 2008 Oct;33(4):767-76.
• [23] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.