Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2TTZPZ)

• DOT Name: Cyclin-dependent kinase 4 inhibitor D (CDKN2D)
• Synonyms: p19-INK4d
• Gene Name: CDKN2D
• Related Disease:
  Epithelial ovarian cancer
  Multiple sclerosis
  Ovarian cancer
  Acute lymphocytic leukaemia
  Acute myelogenous leukaemia
  Alzheimer disease
  Autoimmune disease
  Carcinoma
  Colorectal carcinoma
  Hepatitis C virus infection
  leukaemia
  Leukemia
  Lung cancer
  Lung carcinoma
  Matthew-Wood syndrome
  Medulloblastoma
  Melanoma
  Myelodysplastic syndrome
  Osteoarthritis
  Osteosarcoma
  Ovarian neoplasm
  Pancreatic tumour
  Parkinson disease
  Plasma cell myeloma
  Promyelocytic leukaemia
  Retinoblastoma
  Rheumatoid arthritis
  Ulcerative colitis
  Nasopharyngeal carcinoma
  Pancreatic cancer
  Adult lymphoma
  Advanced cancer
  Amyotrophic lateral sclerosis
  Ankylosing spondylitis
  Crohn disease
  Gastric cancer
  Gastric neoplasm
  Glioma
  Hereditary diffuse gastric adenocarcinoma
  Lymphoma
  Nervous system inflammation
  Neuroblastoma
  Pediatric lymphoma
  Psoriasis
  T-cell leukaemia
• UniProt ID: CDN2D_HUMAN
• PDB ID: 1BD8; 1BI8
• Pfam ID: PF00023 ; PF12796
• Sequence:
  MLLEEVRAGDRLSGAAARGDVQEVRRLLHRELVHPDALNRFGKTALQVMMFGSTAIALEL
  LKQGASPNVQDTSGTSPVHDAARTGFLDTLKVLVEHGADVNVPDGTGALPIHLAVQEGHT
  AVVSFLAAESDLHRRDARGLTPLELALQRGAQDLVDILQGHMVAPL
• Function: Interacts strongly with CDK4 and CDK6 and inhibits them.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  Cell cycle (hsa04110)
• Reactome Pathway:
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  Oncogene Induced Senescence (R-HSA-2559585)
  Cyclin D associated events in G1 (R-HSA-69231)
  Oxidative Stress Induced Senescence (R-HSA-2559580)

Molecular Interaction Atlas (MIA) of This DOT

45 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial ovarian cancer	DIS56MH2	Definitive	Biomarker	[1]
Multiple sclerosis	DISB2WZI	Definitive	Biomarker	[2]
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[3]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[7]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[8]
leukaemia	DISS7D1V	Strong	Biomarker	[9]
Leukemia	DISNAKFL	Strong	Biomarker	[9]
Lung cancer	DISCM4YA	Strong	Posttranslational Modification	[10]
Lung carcinoma	DISTR26C	Strong	Posttranslational Modification	[10]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[11]
Medulloblastoma	DISZD2ZL	Strong	Altered Expression	[12]
Melanoma	DIS1RRCY	Strong	Genetic Variation	[13]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[14]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[15]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[16]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[1]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[17]
Parkinson disease	DISQVHKL	Strong	Biomarker	[18]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[3]
Promyelocytic leukaemia	DISYGG13	Strong	Altered Expression	[19]
Retinoblastoma	DISVPNPB	Strong	Genetic Variation	[20]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[15]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[21]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Altered Expression	[22]
Pancreatic cancer	DISJC981	moderate	Altered Expression	[23]
Adult lymphoma	DISK8IZR	Limited	Genetic Variation	[3]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[24]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[25]
Ankylosing spondylitis	DISRC6IR	Limited	Biomarker	[26]
Crohn disease	DIS2C5Q8	Limited	Biomarker	[21]
Gastric cancer	DISXGOUK	Limited	Biomarker	[27]
Gastric neoplasm	DISOKN4Y	Limited	Biomarker	[27]
Glioma	DIS5RPEH	Limited	Biomarker	[28]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Limited	Biomarker	[27]
Lymphoma	DISN6V4S	Limited	Genetic Variation	[3]
Nervous system inflammation	DISB3X5A	Limited	Biomarker	[29]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[30]
Pediatric lymphoma	DIS51BK2	Limited	Genetic Variation	[3]
Psoriasis	DIS59VMN	Limited	Biomarker	[31]
T-cell leukaemia	DISJ6YIF	Limited	Biomarker	[32]

26 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 Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[33]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[34]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[35]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[36]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[37]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[38]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[39]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[40]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[41]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[42]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[43]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[33]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[43]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[27]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[45]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[46]
Cholecalciferol	DMGU74E	Approved	Cholecalciferol increases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[47]
Etretinate	DM2CZFA	Approved	Etretinate increases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[47]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[48]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[49]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[50]
Scriptaid	DM9JZ21	Preclinical	Scriptaid affects the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[51]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[52]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[53]
Milchsaure	DM462BT	Investigative	Milchsaure affects the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[54]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Cyclin-dependent kinase 4 inhibitor D (CDKN2D).	[42]

References

• [1] Overexpression of WDFY2 inhibits prostate cancer cell growth and migration via inactivation of Akt pathway.Tumour Biol. 2017 Jun;39(6):1010428317704821. doi: 10.1177/1010428317704821.
• [2] Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia.Brain. 2007 Feb;130(Pt 2):490-501. doi: 10.1093/brain/awl273. Epub 2006 Sep 26.
• [3] Alterations of the cyclin-dependent kinase inhibitor p19 (INK4D) is rare in hematopoietic malignancies.Leukemia. 1996 Dec;10(12):1897-900.
• [4] The small chaperone protein p23 and its cleaved product p19 in cellular stress.J Mol Neurosci. 2012 Feb;46(2):303-14. doi: 10.1007/s12031-011-9574-7. Epub 2011 Jun 21.
• [5] IL-23 and Th17 Disease in Inflammatory Arthritis.J Clin Med. 2017 Aug 29;6(9):81. doi: 10.3390/jcm6090081.
• [6] p19(INK4d) mRNA and protein expression as new prognostic factors in ovarian cancer patients.Cancer Biol Ther. 2013 Oct 1;14(10):973-81. doi: 10.4161/cbt.25966. Epub 2013 Aug 14.
• [7] Investigation of IL-23 (p19, p40) and IL-23R identifies nuclear expression of IL-23 p19 as a favorable prognostic factor in colorectal cancer: a retrospective multicenter study of 675 patients.Oncotarget. 2014 Jul 15;5(13):4671-82. doi: 10.18632/oncotarget.2069.
• [8] The identification of three sizes of core proteins during the establishment of persistent hepatitis C virus infection in vitro.Virol Sin. 2013 Jun;28(3):129-35. doi: 10.1007/s12250-013-3296-7. Epub 2013 Mar 25.
• [9] Review of alterations of the cyclin-dependent kinase inhibitor INK4 family genes p15, p16, p18 and p19 in human leukemia-lymphoma cells.Leukemia. 1998 Jun;12(6):845-59. doi: 10.1038/sj.leu.2401043.
• [10] Increased expression of unmethylated CDKN2D by 5-aza-2'-deoxycytidine in human lung cancer cells.Oncogene. 2001 Nov 22;20(53):7787-96. doi: 10.1038/sj.onc.1204970.
• [11] Targeted Delivery of C/EBP -saRNA by Pancreatic Ductal Adenocarcinoma-specific RNA Aptamers Inhibits Tumor Growth In Vivo.Mol Ther. 2016 Jun;24(6):1106-1116. doi: 10.1038/mt.2016.60. Epub 2016 Mar 17.
• [12] A molecular fingerprint for medulloblastoma.Cancer Res. 2003 Sep 1;63(17):5428-37.
• [13] Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors.Cancer Res. 1998 Jun 1;58(11):2298-303.
• [14] Molecular analysis of the cyclin-dependent kinase inhibitor genes, p15, p16, p18 and p19 in the myelodysplastic syndromes.Leuk Res. 1997 Mar;21(3):235-40. doi: 10.1016/s0145-2126(96)00115-4.
• [15] Abundant expression of the interleukin (IL)23 subunit p19, but low levels of bioactive IL23 in the rheumatoid synovium: differential expression and Toll-like receptor-(TLR) dependent regulation of the IL23 subunits, p19 and p40, in rheumatoid arthritis.Ann Rheum Dis. 2009 Jan;68(1):143-50. doi: 10.1136/ard.2007.082081. Epub 2008 Feb 14.
• [16] Structure of human cyclin-dependent kinase inhibitor p19INK4d: comparison to known ankyrin-repeat-containing structures and implications for the dysfunction of tumor suppressor p16INK4a.Structure. 1998 Oct 15;6(10):1279-90. doi: 10.1016/s0969-2126(98)00128-2.
• [17] Tumor suppressor genes in the 9p21 gene cluster are selective targets of inactivation in neuroendocrine gastroenteropancreatic tumors.Cancer Res. 2001 Aug 1;61(15):5905-10.
• [18] Downregulated expression of microRNA-329 inhibits apoptosis of nigral dopaminergic neurons by regulating CDKN2D expression via the FoxO3a signaling pathway in rats with Parkinson's disease.J Cell Physiol. 2018 Nov;233(11):8617-8629. doi: 10.1002/jcp.26608. Epub 2018 May 15.
• [19] E2f1 regulates the induction of promyelocytic leukemia zinc finger transcription in neuronal differentiation of pluripotent P19 embryonal carcinoma cells.Biochem Biophys Res Commun. 2019 May 7;512(3):629-634. doi: 10.1016/j.bbrc.2019.03.058. Epub 2019 Mar 23.
• [20] Regulated expression of the retinoblastoma gene in differentiating embryonal carcinoma cells.Oncogene. 1993 Jun;8(6):1585-91.
• [21] IL-23 in inflammatory bowel diseases and colon cancer.Cytokine Growth Factor Rev. 2019 Feb;45:1-8. doi: 10.1016/j.cytogfr.2018.12.002. Epub 2018 Dec 12.
• [22] Identification of aberrant cell cycle regulation in Epstein-Barr virus-associated nasopharyngeal carcinoma by cDNA microarray and gene set enrichment analysis.Acta Biochim Biophys Sin (Shanghai). 2009 May;41(5):414-28. doi: 10.1093/abbs/gmp025.
• [23] Aptamer-Drug Conjugates of Active Metabolites of Nucleoside Analogs and Cytotoxic Agents Inhibit Pancreatic Tumor Cell Growth.Mol Ther Nucleic Acids. 2017 Mar 17;6:80-88. doi: 10.1016/j.omtn.2016.11.008. Epub 2016 Dec 10.
• [24] The role of p19 and p21 H-Ras proteins and mutants in miRNA expression in cancer and a Costello syndrome cell model.BMC Med Genet. 2015 Jul 3;16:46. doi: 10.1186/s12881-015-0184-z.
• [25] Human angiogenin is a neuroprotective factor and amyotrophic lateral sclerosis associated angiogenin variants affect neurite extension/pathfinding and survival of motor neurons.Hum Mol Genet. 2008 Jan 1;17(1):130-49. doi: 10.1093/hmg/ddm290. Epub 2007 Oct 4.
• [26] Risankizumab, an IL-23 inhibitor, for ankylosing spondylitis: results of a randomised, double-blind, placebo-controlled, proof-of-concept, dose-finding phase 2 study.Ann Rheum Dis. 2018 Sep;77(9):1295-1302. doi: 10.1136/annrheumdis-2018-213328. Epub 2018 Jun 26.
• [27] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [28] Antitumour effect of cyclin-dependent kinase inhibitors (p16(INK4A), p18(INK4C), p19(INK4D), p21(WAF1/CIP1) and p27(KIP1)) on malignant glioma cells.Br J Cancer. 2003 Apr 22;88(8):1277-80. doi: 10.1038/sj.bjc.6600862.
• [29] Tolerogenic dendritic cells produced by lentiviral-mediated CD40- and interleukin-23p19-specific shRNA can ameliorate experimental autoimmune encephalomyelitis by suppressing T helper type 17 cells.Clin Exp Immunol. 2014 May;176(2):180-9. doi: 10.1111/cei.12266.
• [30] p19-INK4d inhibits neuroblastoma cell growth, induces differentiation and is hypermethylated and downregulated in MYCN-amplified neuroblastomas.Hum Mol Genet. 2014 Dec 20;23(25):6826-37. doi: 10.1093/hmg/ddu406. Epub 2014 Aug 7.
• [31] Tildrakizumab: A Review in Moderate-to-Severe Plaque Psoriasis.Am J Clin Dermatol. 2019 Apr;20(2):295-306. doi: 10.1007/s40257-019-00435-9.
• [32] Frequent lack of antibodies against human T-cell leukemia virus type I gag proteins p24 or p19 in sera of patients with adult T-cell leukemia.J Cancer Res Clin Oncol. 1989;115(3):279-84. doi: 10.1007/BF00391703.
• [33] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [34] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [35] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [36] 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.
• [37] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [38] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [39] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [40] Application of cDNA microarray to the study of arsenic-induced liver diseases in the population of Guizhou, China. Toxicol Sci. 2001 Jan;59(1):185-92.
• [41] Arsenic trioxide and cisplatin synergism increase cytotoxicity in human ovarian cancer cells: therapeutic potential for ovarian cancer. Cancer Sci. 2009 Dec;100(12):2459-64.
• [42] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [43] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [44] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [45] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [46] Simvastatin inhibits cell growth and induces apoptosis and G0/G1 cell cycle arrest in hepatic cancer cells. Int J Mol Med. 2010 Nov;26(5):735-41. doi: 10.3892/ijmm_00000520.
• [47] p19INK4D and cell death. Cell Cycle. 2006 Mar;5(6):596-8. doi: 10.4161/cc.5.6.2585. Epub 2006 Mar 15.
• [48] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [49] 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.
• [50] 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.
• [51] Histone deacetylase inhibitor scriptaid induces cell cycle arrest and epigenetic change in colon cancer cells. Int J Oncol. 2008 Oct;33(4):767-76.
• [52] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [53] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [54] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.