Details of Drug Off-Target (DOT)

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

• DOT Name: Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1)
• Synonyms: CDK2-associated protein 1; Deleted in oral cancer 1; DOC-1; Putative oral cancer suppressor
• Gene Name: CDK2AP1
• Related Disease:
  Multiple sclerosis
  Primary biliary cholangitis
  Advanced cancer
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Colorectal neoplasm
  Combined oxidative phosphorylation defect type 7
  Epithelial ovarian cancer
  Glioma
  Oral cancer
  Ovarian cancer
  Ovarian neoplasm
  Prostate cancer
  Prostate carcinoma
  Spinal muscular atrophy
  Squamous cell carcinoma
  Typhoid fever
  Allergic rhinitis
  Carcinoma
  Gastroenteritis
  Head and neck cancer
  Head and neck carcinoma
  Laryngeal squamous cell carcinoma
  Nasopharyngeal carcinoma
• UniProt ID: CDKA1_HUMAN
• PDB ID: 2KW6
• Pfam ID: PF09806
• Sequence:
  MSYKPNLAAHMPAAALNAAGSVHSPSTSMATSSQYRQLLSDYGPPSLGYTQGTGNSQVPQ
  SKYAELLAIIEELGKEIRPTYAGSKSAMERLKRGIIHARGLVRECLAETERNARS
• Function: Inhibitor of cyclin-dependent kinase CDK2. Also acts as a component of the histone deacetylase NuRD complex which participates in the remodeling of chromatin.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Multiple sclerosis	DISB2WZI	Definitive	Biomarker	[1]
Primary biliary cholangitis	DIS43E0O	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[6]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[7]
Combined oxidative phosphorylation defect type 7	DISZ2YBE	Strong	Genetic Variation	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[9]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Oral cancer	DISLD42D	Strong	Biomarker	[10]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[9]
Prostate cancer	DISF190Y	Strong	Altered Expression	[11]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[11]
Spinal muscular atrophy	DISTLKOB	Strong	Genetic Variation	[12]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[13]
Typhoid fever	DISP3NHR	Strong	Genetic Variation	[14]
Allergic rhinitis	DIS3U9HN	moderate	Genetic Variation	[15]
Carcinoma	DISH9F1N	moderate	Biomarker	[16]
Gastroenteritis	DISXQCG5	moderate	Biomarker	[17]
Head and neck cancer	DISBPSQZ	moderate	Biomarker	[16]
Head and neck carcinoma	DISOU1DS	moderate	Biomarker	[16]
Laryngeal squamous cell carcinoma	DIS9UUVF	moderate	Altered Expression	[18]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1).	[21]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1).	[23]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1).	[25]
Scriptaid	DM9JZ21	Preclinical	Scriptaid affects the expression of Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1).	[27]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Cyclin-dependent kinase 2-associated protein 1 (CDK2AP1).	[28]

References

• [1] IL12A, MPHOSPH9/CDK2AP1 and RGS1 are novel multiple sclerosis susceptibility loci.Genes Immun. 2010 Jul;11(5):397-405. doi: 10.1038/gene.2010.28. Epub 2010 Jun 17.
• [2] miRNA-21 ablation protects against liver injury and necroptosis in cholestasis.Cell Death Differ. 2018 May;25(5):857-872. doi: 10.1038/s41418-017-0019-x. Epub 2017 Dec 11.
• [3] Knockdown of CDK2AP1 by RNA interference inhibits cell growth and tumorigenesis of human glioma.Neurol Res. 2014 Jul;36(7):659-65. doi: 10.1179/1743132813Y.0000000298. Epub 2013 Dec 19.
• [4] Effectiveness of the Chest Strap Electrocardiogram to Detect Atrial Fibrillation.Am J Cardiol. 2019 May 15;123(10):1643-1648. doi: 10.1016/j.amjcard.2019.02.028. Epub 2019 Feb 23.
• [5] mRNA Expression of CDK2AP1 in Human Breast Cancer: Correlation with Clinical and Pathological Parameters.Cancer Genomics Proteomics. 2018 Nov-Dec;15(6):447-452. doi: 10.21873/cgp.20103.
• [6] Modulation of CDK2-AP1 (p12(DOC-1)) expression in human colorectal cancer.Oncogene. 2005 May 19;24(22):3657-68. doi: 10.1038/sj.onc.1208378.
• [7] A del T poly T (8) mutation in the 3' untranslated region (UTR) of the CDK2-AP1 gene is functionally significant causing decreased mRNA stability resulting in decreased CDK2-AP1 expression in human microsatellite unstable (MSI) colorectal cancer (CRC).Surgery. 2007 Aug;142(2):222-7. doi: 10.1016/j.surg.2007.04.002.
• [8] Adult Onset Leigh Syndrome in the Intensive Care Setting: A Novel Presentation of a C12orf65 Related Mitochondrial Disease.J Neuromuscul Dis. 2015 Oct 7;2(4):409-419. doi: 10.3233/JND-150121.
• [9] Molecular cloning of differentially expressed genes in human epithelial ovarian cancer.Gynecol Oncol. 1994 Feb;52(2):247-52. doi: 10.1006/gyno.1994.1040.
• [10] DOC1-Dependent Recruitment of NURD Reveals Antagonism with SWI/SNF during Epithelial-Mesenchymal Transition in Oral Cancer Cells.Cell Rep. 2017 Jul 5;20(1):61-75. doi: 10.1016/j.celrep.2017.06.020.
• [11] Cell cycle regulator cdk2ap1 inhibits prostate cancer cell growth and modifies androgen-responsive pathway function.Prostate. 2009 Oct 1;69(14):1586-97. doi: 10.1002/pros.21007.
• [12] DYNC1H1 gene methylation correlates with severity of spinal muscular atrophy.Ann Hum Genet. 2019 Mar;83(2):73-81. doi: 10.1111/ahg.12288. Epub 2018 Sep 24.
• [13] miR-21 downregulates the tumor suppressor P12 CDK2AP1 and stimulates cell proliferation and invasion.J Cell Biochem. 2011 Mar;112(3):872-80. doi: 10.1002/jcb.22995.
• [14] Epidemiology and Genomics of Invasive Nontyphoidal Salmonella Infections in Kenya.Clin Infect Dis. 2015 Nov 1;61 Suppl 4(Suppl 4):S317-24. doi: 10.1093/cid/civ711.
• [15] Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis.Nat Genet. 2018 Aug;50(8):1072-1080. doi: 10.1038/s41588-018-0157-1. Epub 2018 Jul 16.
• [16] Expression of cyclin-dependent kinase 2-associated protein 1 confers an independent prognosticator in nasopharyngeal carcinoma: a cohort study.J Clin Pathol. 2012 Sep;65(9):795-801. doi: 10.1136/jclinpath-2012-200893. Epub 2012 Jul 12.
• [17] Adding function to the genome of African Salmonella Typhimurium ST313 strain D23580.PLoS Biol. 2019 Jan 15;17(1):e3000059. doi: 10.1371/journal.pbio.3000059. eCollection 2019 Jan.
• [18] miR-205 promotes proliferation and invasion of laryngeal squamous cell carcinoma by suppressing CDK2AP1 expression.Biol Res. 2015 Oct 29;48:60. doi: 10.1186/s40659-015-0052-5.
• [19] 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.
• [20] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [21] 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.
• [22] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [23] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [24] 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.
• [25] 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.
• [26] Histone deacetylase inhibitor scriptaid induces cell cycle arrest and epigenetic change in colon cancer cells. Int J Oncol. 2008 Oct;33(4):767-76.
• [27] 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.
• [28] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.