Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ7JBPK)

• DOT Name: Cyclin-K (CCNK)
• Gene Name: CCNK
• Related Disease:
  Neurodevelopmental disorder
  Prostate cancer
  Prostate carcinoma
  Testicular cancer
  Intellectual developmental disorder with hypertelorism and distinctive facies
• UniProt ID: CCNK_HUMAN
• PDB ID: 2I53 ; 4CXA ; 4NST ; 4UN0 ; 5ACB ; 5EFQ ; 6B3E ; 6CKX ; 6TD3 ; 7NXJ ; 7NXK ; 8BU1 ; 8BU2 ; 8BU3 ; 8BU4 ; 8BU5 ; 8BU6 ; 8BU7 ; 8BU9 ; 8BUA ; 8BUB ; 8BUC ; 8BUD ; 8BUE ; 8BUF ; 8BUG ; 8BUH ; 8BUI ; 8BUJ ; 8BUK ; 8BUL ; 8BUM ; 8BUN ; 8BUO ; 8BUP ; 8BUQ ; 8BUR ; 8BUS ; 8BUT ; 8P81
• Pfam ID: PF00134 ; PF21797
• Sequence:
  MKENKENSSPSVTSANLDHTKPCWYWDKKDLAHTPSQLEGLDPATEARYRREGARFIFDV
  GTRLGLHYDTLATGIIYFHRFYMFHSFKQFPRYVTGACCLFLAGKVEETPKKCKDIIKTA
  RSLLNDVQFGQFGDDPKEEVMVLERILLQTIKFDLQVEHPYQFLLKYAKQLKGDKNKIQK
  LVQMAWTFVNDSLCTTLSLQWEPEIIAVAVMYLAGRLCKFEIQEWTSKPMYRRWWEQFVQ
  DVPVDVLEDICHQILDLYSQGKQQMPHHTPHQLQQPPSLQPTPQVPQVQQSQPSQSSEPS
  QPQQKDPQQPAQQQQPAQQPKKPSPQPSSPRQVKRAVVVSPKEENKAAEPPPPKIPKIET
  THPPLPPAHPPPDRKPPLAAALGEAEPPGPVDATDLPKVQIPPPAHPAPVHQPPPLPHRP
  PPPPPSSYMTGMSTTSSYMSGEGYQSLQSMMKTEGPSYGALPPAYGPPAHLPYHPHVYPP
  NPPPPPVPPPPASFPPPAIPPPTPGYPPPPPTYNPNFPPPPPRLPPTHAVPPHPPPGLGL
  PPASYPPPAVPPGGQPPVPPPIPPPGMPPVGGLGRAAWMR
• Function: Regulatory subunit of cyclin-dependent kinases that mediates activation of target kinases. Plays a role in transcriptional regulation via its role in regulating the phosphorylation of the C-terminal domain (CTD) of the large subunit of RNA polymerase II (POLR2A).
• Tissue Specificity: Widely expressed. Highest levels in testis.
• Reactome Pathway:
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  HIV elongation arrest and recovery (R-HSA-167287)
  Pausing and recovery of HIV elongation (R-HSA-167290)
  SMAD2/SMAD3 (R-HSA-2173796)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  RNA polymerase II transcribes snRNA genes (R-HSA-6807505)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[2]
Testicular cancer	DIS6HNYO	Strong	Altered Expression	[3]
Intellectual developmental disorder with hypertelorism and distinctive facies	DISPOVWF	Limited	Autosomal dominant	[4]

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-K (CCNK).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cyclin-K (CCNK).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Cyclin-K (CCNK).	[12]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Cyclin-K (CCNK).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cyclin-K (CCNK).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Cyclin-K (CCNK).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cyclin-K (CCNK).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Cyclin-K (CCNK).	[9]
Marinol	DM70IK5	Approved	Marinol increases the expression of Cyclin-K (CCNK).	[10]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Cyclin-K (CCNK).	[13]
NS398	DMINUWH	Terminated	NS398 decreases the expression of Cyclin-K (CCNK).	[14]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cyclin-K (CCNK).	[15]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Cyclin-K (CCNK).	[16]

References

• [1] De Novo Mutations of CCNK Cause a Syndromic Neurodevelopmental Disorder with Distinctive Facial Dysmorphism. Am J Hum Genet. 2018 Sep 6;103(3):448-455. doi: 10.1016/j.ajhg.2018.07.019. Epub 2018 Aug 16.
• [2] Cyclin K dependent regulation of Aurora B affects apoptosis and proliferation by induction of mitotic catastrophe in prostate cancer.Int J Cancer. 2017 Oct 15;141(8):1643-1653. doi: 10.1002/ijc.30864. Epub 2017 Jul 12.
• [3] A distinct expression pattern of cyclin K in mammalian testes suggests a functional role in spermatogenesis.PLoS One. 2014 Jul 8;9(7):e101539. doi: 10.1371/journal.pone.0101539. eCollection 2014.
• [4] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [5] 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.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):117-27.
• [9] 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.
• [10] Genomic and proteomic analysis of the effects of cannabinoids on normal human astrocytes. Brain Res. 2008 Jan 29;1191:1-11.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Detection of differentially expressed genes in human colon carcinoma cells treated with a selective COX-2 inhibitor. Oncogene. 2001 Jul 27;20(33):4450-6. doi: 10.1038/sj.onc.1204588.
• [15] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [16] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.