Details of Drug Off-Target (DOT)

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

• DOT Name: Cyclin-T1 (CCNT1)
• Synonyms: CycT1; Cyclin-T
• Gene Name: CCNT1
• Related Disease:
  Advanced cancer
  B-cell lymphoma
  Chronic kidney disease
  Cytomegalovirus infection
  HIV infectious disease
  Immunodeficiency
  Influenza
  Astrocytoma
  Neuroblastoma
  Tuberculosis
  Anaplastic large cell lymphoma
  Cardiomyopathy
  Lymphoma
  Neoplasm
• UniProt ID: CCNT1_HUMAN
• PDB ID: 2PK2; 3BLH; 3BLQ; 3BLR; 3LQ5; 3MI9; 3MIA; 3MY1; 3TN8; 3TNH; 3TNI; 4BCF; 4BCG; 4BCH; 4BCI; 4BCJ; 4EC8; 4EC9; 4IMY; 4OGR; 4OR5; 5L1Z; 6CYT; 6GZH; 6W9E; 6Z45; 7NWK; 8K5R
• Pfam ID: PF00134 ; PF21797
• Sequence:
  MEGERKNNNKRWYFTREQLENSPSRRFGVDPDKELSYRQQAANLLQDMGQRLNVSQLTIN
  TAIVYMHRFYMIQSFTQFPGNSVAPAALFLAAKVEEQPKKLEHVIKVAHTCLHPQESLPD
  TRSEAYLQQVQDLVILESIILQTLGFELTIDHPHTHVVKCTQLVRASKDLAQTSYFMATN
  SLHLTTFSLQYTPPVVACVCIHLACKWSNWEIPVSTDGKHWWEYVDATVTLELLDELTHE
  FLQILEKTPNRLKRIWNWRACEAAKKTKADDRGTDEKTSEQTILNMISQSSSDTTIAGLM
  SMSTSTTSAVPSLPVSEESSSNLTSVEMLPGKRWLSSQPSFKLEPTQGHRTSENLALTGV
  DHSLPQDGSNAFISQKQNSKSVPSAKVSLKEYRAKHAEELAAQKRQLENMEANVKSQYAY
  AAQNLLSHHDSHSSVILKMPIEGSENPERPFLEKADKTALKMRIPVAGGDKAASSKPEEI
  KMRIKVHAAADKHNSVEDSVTKSREHKEKHKTHPSNHHHHHNHHSHKHSHSQLPVGTGNK
  RPGDPKHSSQTSNLAHKTYSLSSSFSSSSSTRKRGPSEETGGAVFDHPAKIAKSTKSSSL
  NFSFPSLPTMGQMPGHSSDTSGLSFSQPSCKTRVPHSKLDKGPTGANGHNTTQTIDYQDT
  VNMLHSLLSAQGVQPTQPTAFEFVRPYSDYLNPRSGGISSRSGNTDKPRPPPLPSEPPPP
  LPPLPK
• Function: Regulatory subunit of the cyclin-dependent kinase pair (CDK9/cyclin-T1) complex, also called positive transcription elongation factor B (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNA Pol II). Required to activate the protein kinase activity of CDK9: acts by mediating formation of liquid-liquid phase separation (LLPS) that enhances binding of P-TEFb to the CTD of RNA Pol II ; (Microbial infection) In case of HIV or SIV infections, binds to the transactivation domain of the viral nuclear transcriptional activator, Tat, thereby increasing Tat's affinity for the transactivating response RNA element (TAR RNA). Serves as an essential cofactor for Tat, by promoting RNA Pol II activation, allowing transcription of viral genes.
• Tissue Specificity: Ubiquitously expressed.
• KEGG Pathway:
  Viral life cycle - HIV-1 (hsa03250)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)
  Pausing and recovery of Tat-mediated HIV elongation (R-HSA-167238)
  Tat-mediated HIV elongation arrest and recovery (R-HSA-167243)
  Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246)
  HIV elongation arrest and recovery (R-HSA-167287)
  Pausing and recovery of HIV elongation (R-HSA-167290)
  Interactions of Tat with host cellular proteins (R-HSA-176034)
  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)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[2]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[3]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[4]
HIV infectious disease	DISO97HC	Strong	Altered Expression	[5]
Immunodeficiency	DIS093I0	Strong	Biomarker	[6]
Influenza	DIS3PNU3	Strong	Biomarker	[7]
Astrocytoma	DISL3V18	moderate	Altered Expression	[8]
Neuroblastoma	DISVZBI4	moderate	Altered Expression	[8]
Tuberculosis	DIS2YIMD	Disputed	Altered Expression	[9]
Anaplastic large cell lymphoma	DISP4D1R	Limited	Altered Expression	[10]
Cardiomyopathy	DISUPZRG	Limited	Biomarker	[11]
Lymphoma	DISN6V4S	Limited	Altered Expression	[10]
Neoplasm	DISZKGEW	Limited	Biomarker	[12]

12 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-T1 (CCNT1).	[13]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Cyclin-T1 (CCNT1).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cyclin-T1 (CCNT1).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Cyclin-T1 (CCNT1).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cyclin-T1 (CCNT1).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Cyclin-T1 (CCNT1).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Cyclin-T1 (CCNT1).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Cyclin-T1 (CCNT1).	[20]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Cyclin-T1 (CCNT1).	[19]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Cyclin-T1 (CCNT1).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Cyclin-T1 (CCNT1).	[23]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Cyclin-T1 (CCNT1).	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Cyclin-T1 (CCNT1).	[22]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Cyclin-T1 (CCNT1).	[24]

References

• [1] Ligand- and structure-based pharmacophore modeling, docking study reveals 2-[[4-[6-(isopropylamino) pyrimidin-4-yl]-1H-pyrrolo[2,3-b] pyridin-6-yl] amino] ethanol as a potential anticancer agent of CDK9/cyclin T1 kinase.J Cancer Res Ther. 2019 Jul-Sep;15(5):1131-1140. doi: 10.4103/jcrt.JCRT_47_18.
• [2] EZH2 inhibitors abrogate upregulation of trimethylation of H3K27 by CDK9 inhibitors and potentiate its activity against diffuse large B-cell lymphoma.Haematologica. 2020 Apr;105(4):1021-1031. doi: 10.3324/haematol.2019.222935. Epub 2019 Jul 9.
• [3] The CDK9-cyclin T1 complex mediates saturated fatty acid-induced vascular calcification by inducing expression of the transcription factor CHOP.J Biol Chem. 2018 Nov 2;293(44):17008-17020. doi: 10.1074/jbc.RA118.004706. Epub 2018 Sep 12.
• [4] Recruitment of cdk9 to the immediate-early viral transcriptosomes during human cytomegalovirus infection requires efficient binding to cyclin T1, a threshold level of IE2 86, and active transcription.J Virol. 2009 Jun;83(11):5904-17. doi: 10.1128/JVI.02651-08. Epub 2009 Mar 18.
• [5] Regulation of cyclin T1 during HIV replication and latency establishment in human memory CD4 T cells.Virol J. 2019 Feb 20;16(1):22. doi: 10.1186/s12985-019-1128-6.
• [6] Development of antibody-modified chitosan nanoparticles for the targeted delivery of siRNA across the blood-brain barrier as a strategy for inhibiting HIV replication in astrocytes.Drug Deliv Transl Res. 2017 Aug;7(4):497-506. doi: 10.1007/s13346-017-0368-5.
• [7] Cyclin T1/CDK9 interacts with influenza A virus polymerase and facilitates its association with cellular RNA polymerase II.J Virol. 2010 Dec;84(24):12619-27. doi: 10.1128/JVI.01696-10. Epub 2010 Oct 13.
• [8] Cdk9 regulates neural differentiation and its expression correlates with the differentiation grade of neuroblastoma and PNET tumors. Cancer Biol Ther. 2005 Mar;4(3):277-81. doi: 10.4161/cbt.4.3.1497. Epub 2005 Mar 20.
• [9] Activation of P-TEFb at sites of dual HIV/TB infection, and inhibition of MTB-induced HIV transcriptional activation by the inhibitor of CDK9, Indirubin-3'-monoxime.AIDS Res Hum Retroviruses. 2012 Feb;28(2):182-7. doi: 10.1089/aid.2010.0211. Epub 2011 May 6.
• [10] CDK9/CYCLIN T1 expression during normal lymphoid differentiation and malignant transformation.J Pathol. 2004 Aug;203(4):946-52. doi: 10.1002/path.1588.
• [11] Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure.EMBO J. 2004 Sep 1;23(17):3559-69. doi: 10.1038/sj.emboj.7600351. Epub 2004 Aug 5.
• [12] Cyclin T1 overexpression induces malignant transformation and tumor growth.Cell Cycle. 2010 Aug 1;9(15):3119-26. doi: 10.4161/cc.9.15.12526.
• [13] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [14] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [15] Cdk9 regulates neural differentiation and its expression correlates with the differentiation grade of neuroblastoma and PNET tumors. Cancer Biol Ther. 2005 Mar;4(3):277-81. doi: 10.4161/cbt.4.3.1497. Epub 2005 Mar 20.
• [16] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [17] 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.
• [18] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [19] 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.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [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] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [24] 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.