Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDT45XJ)

• DOT Name: Cell division cycle protein 27 homolog (CDC27)
• Synonyms: Anaphase-promoting complex subunit 3; APC3; CDC27 homolog; CDC27Hs; H-NUC
• Gene Name: CDC27
• Related Disease:
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Prostate neoplasm
  Triple negative breast cancer
  Bone osteosarcoma
  Neoplasm
  Osteosarcoma
  Advanced cancer
  facioscapulohumeral muscular dystrophy
  Gastric cancer
  Stomach cancer
• UniProt ID: CDC27_HUMAN
• PDB ID: 3T1N; 4RG6; 4RG7; 4RG9; 4UI9; 5A31; 5G04; 5G05; 5KHR; 5KHU; 5L9T; 5L9U; 5LCW; 6Q6G; 6Q6H; 6TLJ; 6TM5; 6TNT; 7QE7; 8PKP; 8TAR; 8TAU
• Pfam ID: PF12895 ; PF00515 ; PF13181
• Sequence:
  MTVLQEPVQAAIWQALNHYAYRDAVFLAERLYAEVHSEEALFLLATCYYRSGKAYKAYRL
  LKGHSCTTPQCKYLLAKCCVDLSKLAEGEQILSGGVFNKQKSHDDIVTEFGDSACFTLSL
  LGHVYCKTDRLAKGSECYQKSLSLNPFLWSPFESLCEIGEKPDPDQTFKFTSLQNFSNCL
  PNSCTTQVPNHSLSHRQPETVLTETPQDTIELNRLNLESSNSKYSLNTDSSVSYIDSAVI
  SPDTVPLGTGTSILSKQVQNKPKTGRSLLGGPAALSPLTPSFGILPLETPSPGDGSYLQN
  YTNTPPVIDVPSTGAPSKKSVARIGQTGTKSVFSQSGNSREVTPILAQTQSSGPQTSTTP
  QVLSPTITSPPNALPRRSSRLFTSDSSTTKENSKKLKMKFPPKIPNRKTKSKTNKGGITQ
  PNINDSLEITKLDSSIISEGKISTITPQIQAFNLQKAAAEGLMSLLREMGKGYLALCSYN
  CKEAINILSHLPSHHYNTGWVLCQIGRAYFELSEYMQAERIFSEVRRIENYRVEGMEIYS
  TTLWHLQKDVALSVLSKDLTDMDKNSPEAWCAAGNCFSLQREHDIAIKFFQRAIQVDPNY
  AYAYTLLGHEFVLTEELDKALACFRNAIRVNPRHYNAWYGLGMIYYKQEKFSLAEMHFQK
  ALDINPQSSVLLCHIGVVQHALKKSEKALDTLNKAIVIDPKNPLCKFHRASVLFANEKYK
  SALQELEELKQIVPKESLVYFLIGKVYKKLGQTHLALMNFSWAMDLDPKGANNQIKEAID
  KRYLPDDEEPITQEEQIMGTDESQESSMTDADDTQLHAAESDEF
• 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

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[3]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[4]
Bone osteosarcoma	DIST1004	moderate	Biomarker	[5]
Neoplasm	DISZKGEW	moderate	Altered Expression	[1]
Osteosarcoma	DISLQ7E2	moderate	Biomarker	[5]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[2]
facioscapulohumeral muscular dystrophy	DISSE0H0	Limited	Genetic Variation	[6]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[7]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[7]

17 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 Cell division cycle protein 27 homolog (CDC27).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cell division cycle protein 27 homolog (CDC27).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cell division cycle protein 27 homolog (CDC27).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cell division cycle protein 27 homolog (CDC27).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cell division cycle protein 27 homolog (CDC27).	[12]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cell division cycle protein 27 homolog (CDC27).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cell division cycle protein 27 homolog (CDC27).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Cell division cycle protein 27 homolog (CDC27).	[15]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Cell division cycle protein 27 homolog (CDC27).	[16]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of Cell division cycle protein 27 homolog (CDC27).	[17]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of Cell division cycle protein 27 homolog (CDC27).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Cell division cycle protein 27 homolog (CDC27).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Cell division cycle protein 27 homolog (CDC27).	[19]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Cell division cycle protein 27 homolog (CDC27).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cell division cycle protein 27 homolog (CDC27).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cell division cycle protein 27 homolog (CDC27).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Cell division cycle protein 27 homolog (CDC27).	[24]

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 increases the phosphorylation of Cell division cycle protein 27 homolog (CDC27).	[20]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Cell division cycle protein 27 homolog (CDC27).	[20]

References

• [1] PCBP1/HNRNP E1 Protects Chromosomal Integrity by Translational Regulation of CDC27.Mol Cancer Res. 2016 Jul;14(7):634-46. doi: 10.1158/1541-7786.MCR-16-0018. Epub 2016 Apr 21.
• [2] CDC27 Induces Metastasis and Invasion in Colorectal Cancer via the Promotion of Epithelial-To-Mesenchymal Transition.J Cancer. 2017 Aug 21;8(13):2626-2635. doi: 10.7150/jca.19381. eCollection 2017.
• [3] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [4] MiR-27a modulates radiosensitivity of triple-negative breast cancer (TNBC) cells by targeting CDC27.Med Sci Monit. 2015 May 6;21:1297-303. doi: 10.12659/MSM.893974.
• [5] Whole exome sequencing of a single osteosarcoma case--integrative analysis with whole transcriptome RNA-seq data.Hum Genomics. 2014 Dec 11;8(1):20. doi: 10.1186/s40246-014-0020-0.
• [6] Whole-exome sequencing identifies unique mutations and copy number losses in calcifying fibrous tumor of the pleura: report of 3 cases and review of the literature.Hum Pathol. 2018 Aug;78:36-43. doi: 10.1016/j.humpath.2018.04.005. Epub 2018 Apr 22.
• [7] CDC27 Facilitates Gastric Cancer Cell Proliferation, Invasion and Metastasis via Twist-Induced Epithelial-Mesenchymal Transition.Cell Physiol Biochem. 2018;50(2):501-511. doi: 10.1159/000494164. Epub 2018 Oct 11.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] 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.
• [10] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [11] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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] 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.
• [14] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [15] 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.
• [16] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [17] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [18] Resveratrol-induced gene expression profiles in human prostate cancer cells. Cancer Epidemiol Biomarkers Prev. 2005 Mar;14(3):596-604. doi: 10.1158/1055-9965.EPI-04-0398.
• [19] 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.
• [20] 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.
• [21] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [22] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [23] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.