Details of Drug Off-Target (DOT)

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

• DOT Name: Centrosomal protein of 72 kDa (CEP72)
• Synonyms: Cep72
• Gene Name: CEP72
• Related Disease:
  Peripheral neuropathy
  Acute lymphocytic leukaemia
  Advanced cancer
  Barrett esophagus
  Bladder transitional cell carcinoma
  Childhood acute lymphoblastic leukemia
  Ciliopathy
  Colorectal carcinoma
  Esophageal adenocarcinoma
  Lung adenocarcinoma
  Non-small-cell lung cancer
  Osteosarcoma
• UniProt ID: CEP72_HUMAN
• Pfam ID: PF14580
• Sequence:
  MARAGPRLVLSEEAVRAKSGLGPHRDLAELQSLSIPGTYQEKITHLGHSLMSLTGLKSLD
  LSRNSLVSLEGIQYLTALESLNLYYNCISSLAEVFRLHALTELVDVDFRLNPVVKVEPDY
  RLFVVHLLPKLQQLDDRPVRASERKASRLHFASEDSLDSKESVPASLKEGRPHHPRAKCT
  EALAKQSLVMDADDEAVLNLIAECEWDLGRPPGSTSFSQKGREADSRGSQESRHLLSPQL
  VQYQCGDSGKQGRETRRSSCRGCCLEKMPWSQLCGELPPLYGAEPEASRAPRPHTYFTPH
  PDSMDTEDSASSQKLDLSGEMVPGPLPAPGKCRKRRMPVGRFQTFSDQEGLGCPERTHGS
  SVPKESLSRQDSSESRNGRTLSQPEASETEEQRSRGVTDTREPSPGSHSALPGKKTALQA
  ALLETLLDLVDRSWGGCRSLHSNEAFLAQARHILSSVEEFTAAQDSSAMVGEDVGSLALE
  SKSLQSRLAEQQQQHAREMSEVTAELHHTHKELDDLRQHLDKSLEENSRLKSLLLSMKKE
  VKSADTAATLNLQIAGLQTSVKRLCGEIVELKQHLEHYDKIQELTQMLQESHSSLVSTNE
  HLLQELSQVRAQHRAEVEQMHWSYQELKKTMALFPHSSASHGGCQAC
• Function: Involved in the recruitment of key centrosomal proteins to the centrosome. Provides centrosomal microtubule-nucleation activity on the gamma-tubulin ring complexes (gamma-TuRCs) and has critical roles in forming a focused bipolar spindle, which is needed for proper tension generation between sister chromatids. Required for localization of KIZ, AKAP9 and gamma-tubulin ring complexes (gamma-TuRCs). Involved in centriole duplication. Required for CDK5RAP22, CEP152, WDR62 and CEP63 centrosomal localization and promotes the centrosomal localization of CDK2.
• Reactome Pathway:
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  AURKA Activation by TPX2 (R-HSA-8854518)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Peripheral neuropathy	DIS7KN5G	Definitive	Genetic Variation	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Barrett esophagus	DIS416Y7	Strong	Genetic Variation	[4]
Bladder transitional cell carcinoma	DISNL46A	Strong	Altered Expression	[3]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[2]
Ciliopathy	DIS10G4I	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Esophageal adenocarcinoma	DISODWFP	Strong	Genetic Variation	[4]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[7]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Centrosomal protein of 72 kDa (CEP72).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Centrosomal protein of 72 kDa (CEP72).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Centrosomal protein of 72 kDa (CEP72).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Centrosomal protein of 72 kDa (CEP72).	[12]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Centrosomal protein of 72 kDa (CEP72).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Centrosomal protein of 72 kDa (CEP72).	[15]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Centrosomal protein of 72 kDa (CEP72).	[15]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Centrosomal protein of 72 kDa (CEP72).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Centrosomal protein of 72 kDa (CEP72).	[13]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Centrosomal protein of 72 kDa (CEP72).	[16]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Centrosomal protein of 72 kDa (CEP72).	[17]

References

• [1] Mutation of CEP72 Gene May Predispose Patients to Hepatotoxicity.J Pediatr Hematol Oncol. 2020 Oct;42(7):e634-e636. doi: 10.1097/MPH.0000000000001568.
• [2] Pharmacogenomic and Pharmacotranscriptomic Profiling of Childhood Acute Lymphoblastic Leukemia: Paving the Way to Personalized Treatment.Genes (Basel). 2019 Mar 1;10(3):191. doi: 10.3390/genes10030191.
• [3] Overexpression of CEP72 Promotes Bladder Urothelial Carcinoma Cell Aggressiveness via Epigenetic CREB-Mediated Induction of SERPINE1.Am J Pathol. 2019 Jun;189(6):1284-1297. doi: 10.1016/j.ajpath.2019.02.014. Epub 2019 Apr 4.
• [4] Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.Lancet Oncol. 2016 Oct;17(10):1363-1373. doi: 10.1016/S1470-2045(16)30240-6. Epub 2016 Aug 12.
• [5] The centriolar satellite proteins Cep72 and Cep290 interact and are required for recruitment of BBS proteins to the cilium.Mol Biol Cell. 2012 Sep;23(17):3322-35. doi: 10.1091/mbc.E12-02-0134. Epub 2012 Jul 5.
• [6] The putative oncogene CEP72 inhibits the mitotic function of BRCA1 and induces chromosomal instability.Oncogene. 2016 May 5;35(18):2398-406. doi: 10.1038/onc.2015.290. Epub 2015 Aug 24.
• [7] CEP72-ROS1: A novel ROS1 oncogenic fusion variant in lung adenocarcinoma identified by next-generation sequencing.Thorac Cancer. 2018 May;9(5):652-655. doi: 10.1111/1759-7714.12617. Epub 2018 Mar 8.
• [8] CpG methylation patterns are associated with gene expression variation in osteosarcoma.Mol Med Rep. 2017 Jul;16(1):901-907. doi: 10.3892/mmr.2017.6635. Epub 2017 May 26.
• [9] 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.
• [10] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [13] 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.
• [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] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [17] 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.
• [18] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.