Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKP7TTR)

• DOT Name: Cyclin-dependent kinase 10 (CDK10)
• Synonyms: EC 2.7.11.22; Cell division protein kinase 10; Serine/threonine-protein kinase PISSLRE
• Gene Name: CDK10
• Related Disease:
  Melanoma
  Stomach cancer
  Al Kaissi syndrome
  Biliary tract cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Ciliopathy
  Colorectal carcinoma
  Corpus callosum, agenesis of
  Fanconi anemia complementation group A
  Fanconi's anemia
  Gallbladder cancer
  Gastric cancer
  Glioma
  Hepatocellular carcinoma
  Intellectual disability
  Lung adenocarcinoma
  Nasopharyngeal carcinoma
  Neoplasm
  Oropharyngeal squamous cell carcinoma
  Syndactyly-telecanthus-anogenital and renal malformations syndrome
  Advanced cancer
  Follicular lymphoma
• UniProt ID: CDK10_HUMAN
• EC Number: 2.7.11.22
• Pfam ID: PF00069
• Sequence:
  MAEPDLECEQIRLKCIRKEGFFTVPPEHRLGRCRSVKEFEKLNRIGEGTYGIVYRARDTQ
  TDEIVALKKVRMDKEKDGIPISSLREITLLLRLRHPNIVELKEVVVGNHLESIFLVMGYC
  EQDLASLLENMPTPFSEAQVKCIVLQVLRGLQYLHRNFIIHRDLKVSNLLMTDKGCVKTA
  DFGLARAYGVPVKPMTPKVVTLWYRAPELLLGTTTQTTSIDMWAVGCILAELLAHRPLLP
  GTSEIHQIDLIVQLLGTPSENIWPGFSKLPLVGQYSLRKQPYNNLKHKFPWLSEAGLRLL
  HFLFMYDPKKRATAGDCLESSYFKEKPLPCEPELMPTFPHHRNKRAAPATSEGQSKRCKP
• Function: Cyclin-dependent kinase that phosphorylates the transcription factor ETS2 (in vitro) and positively controls its proteasomal degradation (in cells). Involved in the regulation of actin cytoskeleton organization through the phosphorylation of actin dynamics regulators such as PKN2. Is a negative regulator of ciliogenesis through phosphorylation of PKN2 and promotion of RhoA signaling.

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Melanoma	DIS1RRCY	Definitive	Genetic Variation	[1]
Stomach cancer	DISKIJSX	Definitive	Altered Expression	[2]
Al Kaissi syndrome	DIS79C5V	Strong	Autosomal recessive	[3]
Biliary tract cancer	DISBNYQL	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[5]
Ciliopathy	DIS10G4I	Strong	Genetic Variation	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Corpus callosum, agenesis of	DISO9P40	Strong	Genetic Variation	[6]
Fanconi anemia complementation group A	DIS8PZLI	Strong	Genetic Variation	[8]
Fanconi's anemia	DISGW6Q8	Strong	Genetic Variation	[8]
Gallbladder cancer	DISXJUAF	Strong	Biomarker	[9]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[11]
Intellectual disability	DISMBNXP	Strong	Biomarker	[12]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[13]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Oropharyngeal squamous cell carcinoma	DIS7D7QV	Strong	Biomarker	[14]
Syndactyly-telecanthus-anogenital and renal malformations syndrome	DISZA8BN	Strong	Biomarker	[15]
Advanced cancer	DISAT1Z9	moderate	Biomarker	[16]
Follicular lymphoma	DISVEUR6	Limited	Altered Expression	[17]

18 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 Cyclin-dependent kinase 10 (CDK10).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin affects the expression of Cyclin-dependent kinase 10 (CDK10).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cyclin-dependent kinase 10 (CDK10).	[20]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cyclin-dependent kinase 10 (CDK10).	[21]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Cyclin-dependent kinase 10 (CDK10).	[22]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cyclin-dependent kinase 10 (CDK10).	[23]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Cyclin-dependent kinase 10 (CDK10).	[24]
Selenium	DM25CGV	Approved	Selenium increases the expression of Cyclin-dependent kinase 10 (CDK10).	[25]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Cyclin-dependent kinase 10 (CDK10).	[27]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cyclin-dependent kinase 10 (CDK10).	[28]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Cyclin-dependent kinase 10 (CDK10).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Cyclin-dependent kinase 10 (CDK10).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cyclin-dependent kinase 10 (CDK10).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Cyclin-dependent kinase 10 (CDK10).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Cyclin-dependent kinase 10 (CDK10).	[32]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Cyclin-dependent kinase 10 (CDK10).	[33]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Cyclin-dependent kinase 10 (CDK10).	[34]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Cyclin-dependent kinase 10 (CDK10).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Cyclin-dependent kinase 10 (CDK10).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cyclin-dependent kinase 10 (CDK10).	[29]

References

• [1] Two-stage genome-wide association study identifies a novel susceptibility locus associated with melanoma.Oncotarget. 2017 Mar 14;8(11):17586-17592. doi: 10.18632/oncotarget.15230.
• [2] Downregulated CDK10 expression in gastric cancer: Association with tumor progression and poor prognosis.Mol Med Rep. 2018 May;17(5):6812-6818. doi: 10.3892/mmr.2018.8662. Epub 2018 Mar 1.
• [3] Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Neuron. 2015 Nov 4;88(3):499-513. doi: 10.1016/j.neuron.2015.09.048.
• [4] CDK10 functions as a tumor suppressor gene and regulates survivability of biliary tract cancer cells.Oncol Rep. 2012 Apr;27(4):1266-76. doi: 10.3892/or.2011.1617. Epub 2011 Dec 30.
• [5] The PISSLRE gene: structure, exon skipping, and exclusion as tumor suppressor in breast cancer.Genomics. 1999 Feb 15;56(1):90-7. doi: 10.1006/geno.1998.5676.
• [6] A homozygous deleterious CDK10 mutation in a patient with agenesis of corpus callosum, retinopathy, and deafness.Am J Med Genet A. 2018 Jan;176(1):92-98. doi: 10.1002/ajmg.a.38506. Epub 2017 Nov 12.
• [7] Inactivation of the Kinase Domain of CDK10 Prevents Tumor Growth in a Preclinical Model of Colorectal Cancer, and Is Accompanied by Downregulation of Bcl-2.Mol Cancer Ther. 2017 Oct;16(10):2292-2303. doi: 10.1158/1535-7163.MCT-16-0666. Epub 2017 Jun 29.
• [8] Construction of a high-resolution physical and transcription map of chromosome 16q24.3: a region of frequent loss of heterozygosity in sporadic breast cancer.Genomics. 1998 May 15;50(1):1-8. doi: 10.1006/geno.1998.5316.
• [9] miR-433 accelerates acquired chemoresistance of gallbladder cancer cells by targeting cyclin M.Oncol Lett. 2018 Mar;15(3):3305-3312. doi: 10.3892/ol.2017.7708. Epub 2017 Dec 28.
• [10] Cyclindependent kinase 10 prevents glioma metastasis via modulation of Snail expression.Mol Med Rep. 2018 Jul;18(1):1165-1170. doi: 10.3892/mmr.2018.9059. Epub 2018 May 23.
• [11] Promoter hypermethylation contributes to the frequent suppression of the CDK10 gene in human nasopharyngeal carcinomas.Cell Oncol (Dordr). 2013 Jul;36(4):323-31. doi: 10.1007/s13402-013-0137-5. Epub 2013 Jun 6.
• [12] CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays.Am J Hum Genet. 2017 Sep 7;101(3):391-403. doi: 10.1016/j.ajhg.2017.08.003.
• [13] CDK10 is not a target for aberrant DNA methylation in breast cancer.Anticancer Res. 2009 Oct;29(10):3939-44.
• [14] Genomic Copy Number Variations Characterize the Prognosis of Both P16-Positive and P16-Negative Oropharyngeal Squamous Cell Carcinoma After Curative Resection.Medicine (Baltimore). 2015 Dec;94(50):e2187. doi: 10.1097/MD.0000000000002187.
• [15] STAR syndrome-associated CDK10/Cyclin M regulates actin network architecture and ciliogenesis.Cell Cycle. 2016;15(5):678-88. doi: 10.1080/15384101.2016.1147632.
• [16] The awakening of the CDK10/Cyclin M protein kinase.Oncotarget. 2017 Jul 25;8(30):50174-50186. doi: 10.18632/oncotarget.15024.
• [17] Gene expression profiling of follicular lymphoma and normal germinal center B cells using cDNA arrays.Blood. 2002 Jan 1;99(1):282-9. doi: 10.1182/blood.v99.1.282.
• [18] 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.
• [19] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [20] 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.
• [21] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [22] Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. Lab Anim Res. 2011 Jun;27(2):99-107. doi: 10.5625/lar.2011.27.2.99. Epub 2011 Jun 22.
• [23] Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ Toxicol. 2018 Nov;33(11):1168-1181. doi: 10.1002/tox.22623. Epub 2018 Aug 27.
• [24] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [25] 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.
• [26] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [27] Analysis of gene expression induced by diethylstilbestrol (DES) in human primitive Mullerian duct cells using microarray. Cancer Lett. 2005 Apr 8;220(2):197-210.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] 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.
• [30] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [31] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [32] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [33] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [34] 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.
• [35] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.