Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRH1R55)

• DOT Name: Anaphase-promoting complex subunit 15 (ANAPC15)
• Synonyms: APC15
• Gene Name: ANAPC15
• UniProt ID: APC15_HUMAN
• PDB ID: 4UI9; 5A31; 5G04; 5G05; 5L9T; 5L9U; 5LCW; 6Q6G; 6Q6H; 6TLJ; 6TM5; 6TNT; 7QE7; 8PKP; 8TAR; 8TAU
• Pfam ID: PF15243
• Sequence:
  MSTLFPSLFPRVTETLWFNLDRPCVEETELQQQEQQHQAWLQSIAEKDNNLVPIGKPASE
  HYDDEEEEDDEDDEDSEEDSEDDEDMQDMDEMNDYNESPDDGEVNEVDMEGNEQDQDQWM
  I
• 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. In the complex, plays a role in the release of the mitotic checkpoint complex (MCC) from the APC/C: not required for APC/C activity itself, but promotes the turnover of CDC20 and MCC on the APC/C, thereby participating in the responsiveness of the spindle assembly checkpoint. Also required for degradation of CDC20.
• 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)
  Inactivation of APC/C via direct inhibition of the APC/C complex (R-HSA-141430)

Molecular Interaction Atlas (MIA) of This DOT

11 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 15 (ANAPC15).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Anaphase-promoting complex subunit 15 (ANAPC15).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Anaphase-promoting complex subunit 15 (ANAPC15).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Anaphase-promoting complex subunit 15 (ANAPC15).	[4]
Selenium	DM25CGV	Approved	Selenium increases the expression of Anaphase-promoting complex subunit 15 (ANAPC15).	[5]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Anaphase-promoting complex subunit 15 (ANAPC15).	[5]
PEITC	DMOMN31	Phase 2	PEITC decreases the expression of Anaphase-promoting complex subunit 15 (ANAPC15).	[6]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Anaphase-promoting complex subunit 15 (ANAPC15).	[8]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Anaphase-promoting complex subunit 15 (ANAPC15).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Anaphase-promoting complex subunit 15 (ANAPC15).	[10]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Anaphase-promoting complex subunit 15 (ANAPC15).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Anaphase-promoting complex subunit 15 (ANAPC15).	[7]

References

• [1] 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.
• [2] 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.
• [3] 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.
• [4] 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.
• [5] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [6] Phenethyl isothiocyanate alters the gene expression and the levels of protein associated with cell cycle regulation in human glioblastoma GBM 8401 cells. Environ Toxicol. 2017 Jan;32(1):176-187.
• [7] 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.
• [8] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [9] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [10] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [11] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.