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CHEN Ming, XIE Zhouling, LI Tinghan, WEI Zhihui, ZHAO Lu, LI Zhiyu. Advances in research on a novel antitumor target CDK9 and its inhibitors[J]. Journal of China Pharmaceutical University, 2017, 48(2): 233-241. DOI: 10.11665/j.issn.1000-5048.20170216
Citation: CHEN Ming, XIE Zhouling, LI Tinghan, WEI Zhihui, ZHAO Lu, LI Zhiyu. Advances in research on a novel antitumor target CDK9 and its inhibitors[J]. Journal of China Pharmaceutical University, 2017, 48(2): 233-241. DOI: 10.11665/j.issn.1000-5048.20170216

Advances in research on a novel antitumor target CDK9 and its inhibitors

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  • The cyclin-dependent protein kinase 9(CDK9)is a member of the family of cyclin-dependent protein kinases. Different from other CDKs, CDK9 mainly works on the transcription regulation and has no affects on the cell cycle progress. There are many kinds of CDK9 inhibitors in the clinical research. The detailed structure and action mechanism of CDK9, its difference of protein structure from other CDKs, several selective or nonselective CDK9 inhibitors, as well as their structure-activity relationship(SAR)are discussed in this paper.
  • [1]
    Wang S,Fischer PM. Cyclin-dependent kinase 9:a key transcriptional regulator and potential drug target in oncology,virology and cardiology[J].Trends Pharmacol Sci, 2008,29(6):302-313.
    [2]
    Heathcote DA,Patel H,Kroll SH,et al.A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1,2,and 9,which demonstrates antitumor effects in human tumor xenografts following oral administration[J].J Med Chem,2010,53(24):8508-8522.
    [3]
    Wsierska-Gdek J,Chamrád I,Kryštof V. Novel potent pharmacological cyclin-dependent kinase inhibitors[J].Future Med Chem,2009,1(9):1561-1581.
    [4]
    Kryšof V,Chamrád I,Jorda R,et al.Pharmacological targeting of CDK9 in cardiac hypertrophy[J].Med Res Rev,2010,30(4):646-666.
    [5]
    Chen YJ,Dominguez-Brauer C,Wang Z,et al.A conserved phosphorylation site within the forkhead domain of FoxM1B is required for its activation by cyclin-CDK1[J].J Biol Chem,2009,284(44):30695-30707.
    [6]
    Marais A,Ji Z,Child ES,et al.Cell cycle-dependent regulation of the forkhead transcription factor FOXK2 by CDK·cyclin complexes[J].J Biol Chem,2010,285(46):35728-35739.
    [7]
    Tomashevski A, Webster DR, Grammas P, et al. Cyclin-C-dependent cell-cycle entry is required for activation of non-homologous end joining DNA repair in postmitotic neurons[J].Cell Death Differ,2010,17(7):1189-1198.
    [8]
    Aggarwal P,Vaites LP,Kim JK,et al.Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase[J].Cancer Cell,2010,18(4):329-340.
    [9]
    Lavoie G,St-Pierre Y. Phosphorylation of human DNMT1:implication of cyclin-dependent kinases[J].Biochem Biophys Res Commun,2011,409(2):187-192.
    [10]
    Tudhope SJ,Wang CC,Petrie JL,et al.A novel mechanism for regulating hepatic glycogen synthesis involving serotonin and cyclin-dependent kinase-5[J].Diabetes,2012,61(1):49-60.
    [11]
    Firestein R,Bass AJ,Kim SY,et al.CDK8 is a colorectal cancer oncogene that regulates beta-catenin activity[J].Nature,2008,455(7212):547-551.
    [12]
    Zhao X,Feng D,Wang Q,et al.Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1[J].J Clin Invest,2012,122(7):2417-2427.
    [13]
    Yu DS,Zhao R,Hsu EL,et al.Cyclin-dependent kinase 9-cyclin K functions in the replication stress response[J].EMBO Rep,2010,11(11):876-882.
    [14]
    Kryštof V,Baumli S,Fürst R. Perspective of cyclin-dependent kinase 9(CDK9)as a drug target[J].Curr Pharm Des,2012,18(20):2883-2890.
    [15]
    Stellrecht CM,Chen LS. Transcription inhibition as a therapeutic target for cancer[J].Cancers,2011,3(4):4170-4190.
    [16]
    MacCallum DE,Melville J,Frame S,et al.Seliciclib(CYC202,R-roscovitine)induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1[J].Cancer Res,2005,65(12):5399-5407.
    [17]
    Echalier A,Hole AJ,Lolli G,et al.An inhibitor′s-eye view of the ATP-binding site of CDKs in different regulatory states[J].ACS Chem Biol,2014,9(6):1251-1256.
    [18]
    Echalier A,Endicott JA,Noble ME. Recent developments in cyclin-dependent kinase biochemical and structural studies[J].Biochim Biophys Acta,2010,1804(3):511-519.
    [19]
    Nowicki MW,Walkinshaw MD. CDK9 inhibitors push cancer cells over the edge[J].Chem Biol,2010,17(10):1047-1048.
    [20]
    Baumli S,Lolli G,Lowe ED,et al.The structure of P-TEFb(CDK9/cyclin T1),its complex with flavopiridol and regulation by phosphorylation[J].EMBO J,2008,27(13):1907-1918.
    [21]
    Ahn YM,Vogeti L,Liu CJ,et al.Design,synthesis,and antiproliferative and CDK2-cyclin a inhibitory activity of novel flavopiridol analogues[J].Bioorg Med Chem,2007,15(2):702-713.
    [22]
    Manohar SM, Rathos MJ, Sonawane V, et al. Cyclin-dependent kinase inhibitor,P276-00 induces apoptosis in multiple myeloma cells by inhibition of Cdk9-T1 and RNA polymerase II-dependent transcription[J].Leuk Res,2011,35(6):821-830.
    [23]
    Cassaday RD,Goy A,Advani S,et al.A phase II,single-arm,open-label,multicenter study to evaluate the efficacy and safety of P276-00,a cyclin-dependent kinase inhibitor,in patients with relapsed or refractory mantle cell lymphoma[J].Clin Lymphoma Myeloma Leuk,2015,15(7):392-397.
    [24]
    Houzé S, Hoang NT, Lozach O, et al. Several human cyclin-dependent kinase inhibitors,structurally related to roscovitine,are new anti-malarial agents[J].Molecules,2014,19(9):15237-15257.
    [25]
    Benson C,White J,De Bono J,et al.A phase I trial of the selective oral cyclin-dependent kinase inhibitor seliciclib(CYC202;R-roscovitine),administered twice daily for 7 days every 21 days[J].Br J Cancer,2007,96(1):29-37.
    [26]
    Mita MM,Joy AA,Mita A,et al.Randomized phase II trial of the cyclin-dependent kinase inhibitor dinaciclib(MK-7965)versus capecitabine in patients with advanced breast cancer[J].Clin Breast Cancer,2014,14(3):169-176.
    [27]
    Mitri Z, Karakas C, Wei C, et al. A phase 1 study with dose expansion of the CDK inhibitor dinaciclib(SCH 727965)in combination with epirubicin in patients with metastatic triple negative breast cancer[J].Invest New Drugs,2015,33(4):890-894.
    [28]
    Santo L,Vallet S,Hideshima T,et al.AT7519,a novel small molecule multi-cyclin-dependent kinase inhibitor,induces apoptosis in multiple myeloma via GSK-3beta activation and RNA polymerase II inhibition[J].Oncogene,2010,29(16):2325-2336.
    [29]
    Chen EX, Hotte S, Hirte H, et al. A phase I study of cyclin-dependent kinase inhibitor,AT7519,in patients with advanced cancer:NCIC Clinical Trials Group IND 177[J].British J Cancer,2014,111(12):2262-2267.
    [30]
    Diab S, Eckhardt S, Tan A, et al. A phase I study of R547,a novel,selective inhibitor of cell cycle and transcriptional cyclin dependent kinases(CDKs)[J].J Clin Oncol,2007,25(Suppl):3528.
    [31]
    Baumli S, Endicott JA, Johnson LN. Halogen bonds form the basis for selective P-TEFb inhibition by DRB[J].Chem Biol,2010,17(9):931-936.
    [32]
    Kryštof V,Rárová L,Liebl J,et al.The selective P-TEFb inhibitor CAN508 targets angiogenesis[J].Eur J Med Chem,2011,46(9):4289-4294.
    [33]
    Kryštof V,Chamrád I,Jorda R,et al.Pharmacological targeting of CDK9 in cardiac hypertrophy[J].Med Res Rev,2010,30(4):646-666.
    [34]
    Baumli S,Hole AJ,Noble ME,et al.The CDK9 C-helix exhibits conformational plasticity that may explain the selectivity of CAN508[J].ACS Chem Biol,2012,7(5):811-816.
    [35]
    Shao H,Shi S,Huang S,et al.Substituted 4-(thiazol-5-yl)-2-(phenylamino)pyrimidines are highly active CDK9 inhibitors:synthesis,X-ray crystal structures,structure-activity relationship,and anticancer activities[J].J Med Chem,2013,<
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