Details of Drug Off-Target (DOT)

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

• DOT Name: Anaphase-promoting complex subunit CDC26 (CDC26)
• Synonyms: Anaphase-promoting complex subunit 12; APC12; Cell division cycle protein 26 homolog
• Gene Name: CDC26
• Related Disease: Hepatocellular carcinoma
• UniProt ID: CDC26_HUMAN
• PDB ID: 3HYM; 4UI9; 5A31; 5G04; 5G05; 5KHR; 5KHU; 5L9T; 5L9U; 5LCW; 6Q6G; 6Q6H; 6TLJ; 6TM5; 6TNT; 7QE7; 8PKP; 8TAR; 8TAU
• Pfam ID: PF10471
• Sequence:
  MLRRKPTRLELKLDDIEEFENIRKDLETRKKQKEDVEVVGGSDGEGAIGLSSDPKSREQM
  INDRIGYKPQPKPNNRSSQFGSLEF
• 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. May recruit the E2 ubiquitin-conjugating enzymes to the complex.
• 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

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Anaphase-promoting complex subunit CDC26 (CDC26).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Anaphase-promoting complex subunit CDC26 (CDC26).	[4]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Anaphase-promoting complex subunit CDC26 (CDC26).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Anaphase-promoting complex subunit CDC26 (CDC26).	[3]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Anaphase-promoting complex subunit CDC26 (CDC26).	[5]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Anaphase-promoting complex subunit CDC26 (CDC26).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Anaphase-promoting complex subunit CDC26 (CDC26).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Anaphase-promoting complex subunit CDC26 (CDC26).	[9]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Anaphase-promoting complex subunit CDC26 (CDC26).	[10]

References

• [1] Association of APC, GSTP1 and SOCS1 promoter methylation with the risk of hepatocellular carcinoma: a meta-analysis.Eur J Cancer Prev. 2015 Nov;24(6):470-83. doi: 10.1097/CEJ.0000000000000121.
• [2] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] 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.
• [5] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [6] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [7] 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.
• [8] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [10] Molecular signatures of cytotoxic effects in human embryonic kidney 293?cells treated with single and mixture of ochratoxin A and citrinin. Food Chem Toxicol. 2019 Jan;123:374-384. doi: 10.1016/j.fct.2018.11.015. Epub 2018 Nov 11.