Details of Drug Off-Target (DOT)

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

• DOT Name: Cyclin-dependent kinase 16 (CDK16)
• Synonyms: EC 2.7.11.22; Cell division protein kinase 16; PCTAIRE-motif protein kinase 1; Serine/threonine-protein kinase PCTAIRE-1
• Gene Name: CDK16
• Related Disease:
  B-cell neoplasm
  Breast carcinoma
  Thyroid gland papillary carcinoma
  Advanced cancer
  Bladder cancer
  Gastric cancer
  Glioma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Medulloblastoma
  Neoplasm
  Prostate neoplasm
  Retinopathy
  Schizophrenia
  Tuberculosis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Ductal breast carcinoma in situ
  Isolated congenital microcephaly
  Osteoarthritis
  Pancreatic cancer
  Breast cancer
  Cutaneous melanoma
  Non-small-cell lung cancer
  Cutaneous squamous cell carcinoma
  Intellectual disability
  Intellectual disability, autosomal dominant 40
  Melanoma
  Pneumonia
  Prostate cancer
  X-linked complex neurodevelopmental disorder
• UniProt ID: CDK16_HUMAN
• PDB ID: 3MTL; 5G6V
• EC Number: 2.7.11.22
• Pfam ID: PF12330 ; PF00069
• Sequence:
  MDRMKKIKRQLSMTLRGGRGIDKTNGAPEQIGLDESGGGGGSDPGEAPTRAAPGELRSAR
  GPLSSAPEIVHEDLKMGSDGESDQASATSSDEVQSPVRVRMRNHPPRKISTEDINKRLSL
  PADIRLPEGYLEKLTLNSPIFDKPLSRRLRRVSLSEIGFGKLETYIKLDKLGEGTYATVY
  KGKSKLTDNLVALKEIRLEHEEGAPCTAIREVSLLKDLKHANIVTLHDIIHTEKSLTLVF
  EYLDKDLKQYLDDCGNIINMHNVKLFLFQLLRGLAYCHRQKVLHRDLKPQNLLINERGEL
  KLADFGLARAKSIPTKTYSNEVVTLWYRPPDILLGSTDYSTQIDMWGVGCIFYEMATGRP
  LFPGSTVEEQLHFIFRILGTPTEETWPGILSNEEFKTYNYPKYRAEALLSHAPRLDSDGA
  DLLTKLLQFEGRNRISAEDAMKHPFFLSLGERIHKLPDTTSIFALKEIQLQKEASLRSSS
  MPDSGRPAFRVVDTEF
• Function: Protein kinase that plays a role in vesicle-mediated transport processes and exocytosis. Regulates GH1 release by brain neurons. Phosphorylates NSF, and thereby regulates NSF oligomerization. Required for normal spermatogenesis. Regulates neuron differentiation and dendrite development. Plays a role in the regulation of insulin secretion in response to changes in blood glucose levels. Can phosphorylate CCNY at 'Ser-336' (in vitro).
• Tissue Specificity: Detected in pancreas islets (at protein level). Detected in brain and pancreas.

Molecular Interaction Atlas (MIA) of This DOT

32 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Definitive	Altered Expression	[2]
Thyroid gland papillary carcinoma	DIS48YMM	Definitive	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Bladder cancer	DISUHNM0	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Lung cancer	DISCM4YA	Strong	Altered Expression	[7]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[7]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[10]
Retinopathy	DISB4B0F	Strong	Biomarker	[11]
Schizophrenia	DISSRV2N	Strong	Biomarker	[12]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[13]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[5]
Urinary bladder neoplasm	DIS7HACE	Strong	Genetic Variation	[5]
Ductal breast carcinoma in situ	DISLCJY7	moderate	Biomarker	[14]
Isolated congenital microcephaly	DISUXHZ6	moderate	Altered Expression	[15]
Osteoarthritis	DIS05URM	moderate	Altered Expression	[16]
Pancreatic cancer	DISJC981	moderate	Biomarker	[17]
Breast cancer	DIS7DPX1	Disputed	Altered Expression	[2]
Cutaneous melanoma	DIS3MMH9	Disputed	Biomarker	[18]
Non-small-cell lung cancer	DIS5Y6R9	Disputed	Genetic Variation	[19]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Biomarker	[9]
Intellectual disability	DISMBNXP	Limited	Biomarker	[20]
Intellectual disability, autosomal dominant 40	DISAI0IH	Limited	X-linked	[21]
Melanoma	DIS1RRCY	Limited	Altered Expression	[22]
Pneumonia	DIS8EF3M	Limited	Genetic Variation	[23]
Prostate cancer	DISF190Y	Limited	Biomarker	[9]
X-linked complex neurodevelopmental disorder	DISI3QE9	Limited	X-linked	[24]

4 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 16 (CDK16).	[25]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cyclin-dependent kinase 16 (CDK16).	[26]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cyclin-dependent kinase 16 (CDK16).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cyclin-dependent kinase 16 (CDK16).	[29]

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 affects the phosphorylation of Cyclin-dependent kinase 16 (CDK16).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Cyclin-dependent kinase 16 (CDK16).	[28]

References

• [1] Effects of propofol on proliferation and anti-apoptosis of neuroblastoma SH-SY5Y cell line: new insights into neuroprotection.Brain Res. 2011 Apr 12;1384:42-50. doi: 10.1016/j.brainres.2011.02.004. Epub 2011 Feb 25.
• [2] RNAi-mediated downregulation of CDKL1 inhibits growth and colony-formation ability, promotes apoptosis of human melanoma cells.J Dermatol Sci. 2015 Jul;79(1):57-63. doi: 10.1016/j.jdermsci.2015.03.020. Epub 2015 Apr 9.
• [3] Ang1/Tie2 induces cell proliferation and migration in human papillary thyroid carcinoma via the PI3K/AKT pathway.Oncol Lett. 2018 Jan;15(1):1313-1318. doi: 10.3892/ol.2017.7367. Epub 2017 Nov 8.
• [4] Phosphoregulation of the oncogenic protein regulator of cytokinesis 1 (PRC1) by the atypical CDK16/CCNY complex.Exp Mol Med. 2019 Apr 16;51(4):1-17. doi: 10.1038/s12276-019-0242-2.
• [5] Mutations in FGFR3 and PIK3CA, singly or combined with RAS and AKT1, are associated with AKT but not with MAPK pathway activation in urothelial bladder cancer.Hum Pathol. 2012 Oct;43(10):1573-82. doi: 10.1016/j.humpath.2011.10.026. Epub 2012 Mar 12.
• [6] High expression of PFTK1 in cancer cells predicts poor prognosis in colorectal cancer.Mol Med Rep. 2017 Jul;16(1):224-230. doi: 10.3892/mmr.2017.6560. Epub 2017 May 10.
• [7] CDK16 Phosphorylates and Degrades p53 to Promote Radioresistance and Predicts Prognosis in Lung Cancer.Theranostics. 2018 Jan 1;8(3):650-662. doi: 10.7150/thno.21963. eCollection 2018.
• [8] RNA interference screening identifies a novel role for PCTK1/CDK16 in medulloblastoma with c-Myc amplification.Oncotarget. 2015 Jan 1;6(1):116-29. doi: 10.18632/oncotarget.2699.
• [9] PCTAIRE1/CDK16/PCTK1 is overexpressed in cutaneous squamous cell carcinoma and regulates p27 stability and cell cycle.J Dermatol Sci. 2017 May;86(2):149-157. doi: 10.1016/j.jdermsci.2017.02.281. Epub 2017 Feb 22.
• [10] PCTAIRE1 phosphorylates p27 and regulates mitosis in cancer cells.Cancer Res. 2014 Oct 15;74(20):5795-807. doi: 10.1158/0008-5472.CAN-14-0872. Epub 2014 Sep 9.
• [11] UHX1 and PCTK1: precise characterisation and localisation within a gene-rich region in Xp11.23 and evaluation as candidate genes for retinal diseases mapped to Xp21.1-p11.2.Eur J Hum Genet. 1998 Sep-Oct;6(5):459-66. doi: 10.1038/sj.ejhg.5200207.
• [12] Genetic and pharmacological evidence for schizophrenia-related Disc1 interaction with GSK-3.Synapse. 2011 Mar;65(3):234-48. doi: 10.1002/syn.20839.
• [13] Synthesis and antimycobacterial activity of imidazo[1,2-b][1,2,4,5]tetrazines.Eur J Med Chem. 2019 Sep 15;178:39-47. doi: 10.1016/j.ejmech.2019.05.081. Epub 2019 May 31.
• [14] Analysis of gene expression in ductal carcinoma in situ of the breast.Clin Cancer Res. 2002 Dec;8(12):3788-95.
• [15] Genetic variation in MKL2 and decreased downstream PCTAIRE1 expression in extreme, fatal primary human microcephaly.Clin Genet. 2014 May;85(5):423-32. doi: 10.1111/cge.12197. Epub 2013 Jun 18.
• [16] Effect of silibinin on CFLAR-JNK pathway in oleic acid-treated HepG2 cells.Biomed Pharmacother. 2018 Dec;108:716-723. doi: 10.1016/j.biopha.2018.09.089. Epub 2018 Sep 21.
• [17] Primate-specific miRNA-637 inhibited tumorigenesis in human pancreatic ductal adenocarcinoma cells by suppressing Akt1 expression.Exp Cell Res. 2018 Feb 15;363(2):310-314. doi: 10.1016/j.yexcr.2018.01.026.
• [18] Long-term Survival of Stage IV Melanoma Patients Treated with BOLD Combination Chemotherapy and Intermediate-dose Subcutaneous Interferon-alpha.Anticancer Res. 2018 Nov;38(11):6393-6397. doi: 10.21873/anticanres.12999.
• [19] Drug resistance to targeted therapeutic strategies in non-small cell lung cancer.Pharmacol Ther. 2020 Feb;206:107438. doi: 10.1016/j.pharmthera.2019.107438. Epub 2019 Nov 9.
• [20] X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes. Mol Psychiatry. 2016 Jan;21(1):133-48. doi: 10.1038/mp.2014.193. Epub 2015 Feb 3.
• [21] Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X. Nat Commun. 2022 Nov 2;13(1):6570. doi: 10.1038/s41467-022-34264-y.
• [22] Dabrafenib inhibits the growth of BRAF-WT cancers through CDK16 and NEK9 inhibition.Mol Oncol. 2018 Jan;12(1):74-88. doi: 10.1002/1878-0261.12152. Epub 2017 Nov 23.
• [23] Discovery of a novel class of highly conserved vaccine antigens using genomic scale antigenic fingerprinting of pneumococcus with human antibodies.J Exp Med. 2008 Jan 21;205(1):117-31. doi: 10.1084/jem.20071168. Epub 2007 Dec 31.
• [24] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [25] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [26] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [27] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [28] 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.
• [29] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.