Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT385ZH1)

• DOT Name: Cyclin-dependent kinase 14 (CDK14)
• Synonyms: EC 2.7.11.22; Cell division protein kinase 14; Serine/threonine-protein kinase PFTAIRE-1; hPFTAIRE1
• Gene Name: CDK14
• Related Disease:
  Glioma
  Hepatitis B virus infection
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Epithelial ovarian cancer
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Gastric cancer
  Matthew-Wood syndrome
  Neoplasm of esophagus
  Ovarian cancer
  Ovarian neoplasm
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  Acute myelogenous leukaemia
  Common variable immunodeficiency
  Hepatocellular carcinoma
  Non-small-cell lung cancer
• UniProt ID: CDK14_HUMAN
• EC Number: 2.7.11.22
• Pfam ID: PF00069
• Sequence:
  MCDLIEPQPAEKIGKMKKLRRTLSESFSRIALKKDDTTFDEICVTKMSTRNCQGMDSVIK
  PLDTIPEDKKVRVQRTQSTFDPFEKPANQVKRVHSENNACINFKTSSTGKESPKVRRHSS
  PSSPTSPKFGKADSYEKLEKLGEGSYATVYKGKSKVNGKLVALKVIRLQEEEGTPFTAIR
  EASLLKGLKHANIVLLHDIIHTKETLTLVFEYVHTDLCQYMDKHPGGLHPDNVKLFLFQL
  LRGLSYIHQRYILHRDLKPQNLLISDTGELKLADFGLARAKSVPSHTYSNEVVTLWYRPP
  DVLLGSTEYSTCLDMWGVGCIFVEMIQGVAAFPGMKDIQDQLERIFLVLGTPNEDTWPGV
  HSLPHFKPERFTLYSSKNLRQAWNKLSYVNHAEDLASKLLQCSPKNRLSAQAALSHEYFS
  DLPPRLWELTDMSSIFTVPNVRLQPEAGESMRAFGKNNSYGKSLSNSKH
• Function: Serine/threonine-protein kinase involved in the control of the eukaryotic cell cycle, whose activity is controlled by an associated cyclin. Acts as a cell-cycle regulator of Wnt signaling pathway during G2/M phase by mediating the phosphorylation of LRP6 at 'Ser-1490', leading to the activation of the Wnt signaling pathway. Acts as a regulator of cell cycle progression and cell proliferation via its interaction with CCDN3. Phosphorylates RB1 in vitro, however the relevance of such result remains to be confirmed in vivo. May also play a role in meiosis, neuron differentiation and may indirectly act as a negative regulator of insulin-responsive glucose transport.
• Tissue Specificity: Highly expressed in brain, pancreas, kidney, heart, testis and ovary. Also detected at lower levels in other tissues except in spleen and thymus where expression is barely detected.
• KEGG Pathway: Transcriptio.l misregulation in cancer (hsa05202)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Biomarker	[1]
Hepatitis B virus infection	DISLQ2XY	Definitive	Genetic Variation	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[5]
Colon cancer	DISVC52G	Strong	Biomarker	[6]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[7]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[8]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[9]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[7]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[10]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[5]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[8]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[8]
Pancreatic cancer	DISJC981	Strong	Biomarker	[10]
Prostate cancer	DISF190Y	Strong	Altered Expression	[11]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[11]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[12]
Common variable immunodeficiency	DISHE7JQ	Limited	Genetic Variation	[13]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[14]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Cyclin-dependent kinase 14 (CDK14).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cyclin-dependent kinase 14 (CDK14).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Cyclin-dependent kinase 14 (CDK14).	[25]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Cyclin-dependent kinase 14 (CDK14).	[28]

11 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 14 (CDK14).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cyclin-dependent kinase 14 (CDK14).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cyclin-dependent kinase 14 (CDK14).	[19]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cyclin-dependent kinase 14 (CDK14).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Cyclin-dependent kinase 14 (CDK14).	[21]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Cyclin-dependent kinase 14 (CDK14).	[23]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Cyclin-dependent kinase 14 (CDK14).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cyclin-dependent kinase 14 (CDK14).	[26]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Cyclin-dependent kinase 14 (CDK14).	[27]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Cyclin-dependent kinase 14 (CDK14).	[29]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone decreases the expression of Cyclin-dependent kinase 14 (CDK14).	[30]

References

• [1] MicroRNA-613 impedes the proliferation and invasion of glioma cells by targeting cyclin-dependent kinase 14.Biomed Pharmacother. 2018 Feb;98:636-642. doi: 10.1016/j.biopha.2017.12.044. Epub 2017 Dec 29.
• [2] Genome-Wide Association Study Identifies a New Locus at 7q21.13 Associated with Hepatitis B Virus-Related Hepatocellular Carcinoma.Clin Cancer Res. 2018 Feb 15;24(4):906-915. doi: 10.1158/1078-0432.CCR-17-2537. Epub 2017 Dec 15.
• [3] LncRNA H19/miR-194/PFTK1 axis modulates the cell proliferation and migration of pancreatic cancer.J Cell Biochem. 2019 Mar;120(3):3874-3886. doi: 10.1002/jcb.27669. Epub 2018 Nov 26.
• [4] Downregulation of dual-specificity tyrosine-regulated kinase 2 promotes tumor cell proliferation and invasion by enhancing cyclin-dependent kinase 14 expression in breast cancer.Cancer Sci. 2018 Feb;109(2):363-372. doi: 10.1111/cas.13459. Epub 2018 Jan 13.
• [5] PFTK1 Promotes Gastric Cancer Progression by Regulating Proliferation, Migration and Invasion.PLoS One. 2015 Oct 21;10(10):e0140451. doi: 10.1371/journal.pone.0140451. eCollection 2015.
• [6] Knockdown of PFTAIRE Protein Kinase 1 (PFTK1) Inhibits Proliferation, Invasion, and EMT in Colon Cancer Cells.Oncol Res. 2016;24(3):137-44. doi: 10.3727/096504016X14611963142218.
• [7] 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.
• [8] MiR-542-3p, a microRNA targeting CDK14, suppresses cell proliferation, invasiveness, and tumorigenesis of epithelial ovarian cancer.Biomed Pharmacother. 2019 Feb;110:850-856. doi: 10.1016/j.biopha.2018.11.104. Epub 2018 Dec 14.
• [9] Overexpression of PFTK1 predicts resistance to chemotherapy in patients with oesophageal squamous cell carcinoma.Br J Cancer. 2012 Feb 28;106(5):947-54. doi: 10.1038/bjc.2012.35. Epub 2012 Feb 14.
• [10] The role of lncRNA MSC-AS1/miR-29b-3p axis-mediated CDK14 modulation in pancreatic cancer proliferation and Gemcitabine-induced apoptosis.Cancer Biol Ther. 2019;20(6):729-739. doi: 10.1080/15384047.2018.1529121. Epub 2019 Mar 27.
• [11] The putative tumour suppressor miR-1-3p modulates prostate cancer cell aggressiveness by repressing E2F5 and PFTK1.J Exp Clin Cancer Res. 2018 Sep 5;37(1):219. doi: 10.1186/s13046-018-0895-z.
• [12] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [13] Genome-wide association identifies diverse causes of common variable immunodeficiency.J Allergy Clin Immunol. 2011 Jun;127(6):1360-7.e6. doi: 10.1016/j.jaci.2011.02.039. Epub 2011 Apr 17.
• [14] LINC00707 contributes to hepatocellular carcinoma progression via sponging miR-206 to increase CDK14.J Cell Physiol. 2019 Jul;234(7):10615-10624. doi: 10.1002/jcp.27737. Epub 2018 Nov 29.
• [15] Long non-coding RNA SNHG15 promotes CDK14 expression via miR-486 to accelerate non-small cell lung cancer cells progression and metastasis.J Cell Physiol. 2018 Sep;233(9):7164-7172. doi: 10.1002/jcp.26543. Epub 2018 Apr 6.
• [16] 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.
• [17] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [18] 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.
• [19] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [25] 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.
• [26] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [27] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [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] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [30] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.