Perspective of cyclin-dependent kinase 9 (CDK9) as a drug target
Jazyk angličtina Země Spojené arabské emiráty Médium print
Typ dokumentu časopisecké články, práce podpořená grantem, přehledy
Grantová podpora
G0901526
Medical Research Council - United Kingdom
PubMed
22571657
PubMed Central
PMC3382371
DOI
10.2174/138161212800672750
PII: CPD-EPUB-20120504-004
Knihovny.cz E-zdroje
- MeSH
- cyklin-dependentní kinasa 9 antagonisté a inhibitory metabolismus MeSH
- inhibitory proteinkinas farmakologie MeSH
- lékové transportní systémy * MeSH
- lidé MeSH
- nádory farmakoterapie enzymologie MeSH
- protinádorové látky farmakologie MeSH
- racionální návrh léčiv MeSH
- zánět enzymologie patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- cyklin-dependentní kinasa 9 MeSH
- inhibitory proteinkinas MeSH
- protinádorové látky MeSH
Deregulation of cyclin-dependent kinases (CDKs) has been associated with many cancer types and has evoked an interest in chemical inhibitors with possible therapeutic benefit. While most known inhibitors display broad selectivity towards multiple CDKs, recent work highlights CDK9 as the critical target responsible for the anticancer activity of clinically evaluated drugs. In this review, we discuss recent findings provided by structural biologists that may allow further development of highly specific inhibitors of CDK9 towards applications in cancer therapy. We also highlight the role of CDK9 in inflammatory processes and diseases.
Zobrazit více v PubMed
Loyer P, Trembley JH, Katona R, Kidd VJ, Lahti JM. Role of CDK/cyclin complexes in transcription and RNA splicing. Cell Signal. 2005;17:1033–51. PubMed
Yu DS, Cortez D. A role for cdk9-cyclin k in maintaining genome integrity. Cell Cycle. 2011;10:28–32. PubMed PMC
Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem Sci. 2005;30:630–41. PubMed
Romano G, Giordano A. Role of the cyclin-dependent kinase 9- related pathway in mammalian gene expression and human diseases. Cell Cycle. 2008;7:3664–8. PubMed
Nechaev S, Adelman K. Pol II waiting in the starting gates: Regulating the transition from transcription initiation into productive elongation. Biochim Biophys Acta. 2011;1809:34–45. PubMed PMC
Wada T, Takagi T, Yamaguchi Y, Watanabe D, Handa H. Evidence that P-TEFb alleviates the negative effect of DSIF on RNA polymerase II-dependent transcription in vitro. EMBO J . 1998;17:7395–403. PubMed PMC
Rahl PB, Lin CY, Seila AC, et al. c-Myc regulates transcriptional pause release. Cell. 2010;141:432–45. PubMed PMC
Barboric M, Nissen RM, Kanazawa S, Jabrane-Ferrat N, Peterlin BM. NF-kappa B binds P-TEFb to stimulate transcriptional elongation by RNA polymerase II. Mol Cell. 2001;8:327–37. PubMed
Lee DK, Duan HO, Chang CS. Androgen receptor interacts with the positive elongation factor P-TEFb and enhances the efficiency of transcriptional elongation. J Biol Chem. 2001;276:9978–84. PubMed
Jang MK, Mochizuki K, Zhou M, Jeong HS, Brady JN, Ozato K. The bromodomain protein Brd4 is a positive regulatory component of P-TEFb and stimulates RNA polymerase II-dependent transcription. Mol Cell. 2005;19:523–34. PubMed
Yang Z, Yik JH, Chen R, et al. Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell. 2005;19:535–45. PubMed
Sobhian B, Laguette N, Yatim A, et al. HIV-1 Tat assembles a multifunctional transcription elongation complex and stably associates with the 7SK snRNP. Mol Cell. 2010;38:439–51. PubMed PMC
Lin C, Smith ER, Takahashi H, et al. AFF4 a component of the ELL/P-TEFb elongation complex and a shared subunit of MLL chimeras, can link transcription elongation to leukemia. Mol Cell . 2010;37:429–37. PubMed PMC
Mueller D, Bach C, Zeisig D, et al. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood. 2007;110:4445–54. PubMed PMC
Yang Z, Zhu Q, Luo K, Zhou Q. The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription. Nature . 2001;414:317–22. PubMed
Michels AA, Nguyen VT, Fraldi A, et al. MAQ1 and 7SK RNA interact with CDK9/cyclin T complexes in a transcription-dependent manner. Mol Cell Biol. 2003;23:4859–69. PubMed PMC
Krueger BJ, Jeronimo C, Roy BB, et al. LARP7 is a stable component of the 7SK snRNP while P-TEFb, HEXIM1 and hnRNP A1 are reversibly associated. Nucleic Acids Res. 2008;36:2219–29. PubMed PMC
Fisher RP. Secrets of a double agent: CDK7 in cell-cycle control and transcription. J Cell Sci. 2005;118:5171–80. PubMed
Bartkowiak B, Liu PD, et al. CDK12 is a transcription elongation-associated CTD kinase, the metazoan ortholog of yeast Ctk1. Genes Dev. 2010;24:2303–16. PubMed PMC
Blazek D, Kohoutek J, Bartholomeeusen K, et al. The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes Dev. 2011;25:2158–72. PubMed PMC
Malumbres M, Barbacid M. Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66. PubMed
Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009;8:547–66. PubMed
Krystof V, Uldrijan S. Cyclin-dependent kinase inhibitors as anticancer drugs. Curr Drug Targets. 2010;11:291–302. PubMed
Chao SH, Price DH. Flavopiridol inactivates P-TEFb and blocks most RNA polymerase II transcription in vivo. J Biol Chem. 2001; 276:31793–9. PubMed
Cai D, Latham VM , Jr , Zhang X, Shapiro GI. Combined depletion of cell cycle and transcriptional cyclin-dependent kinase activities induces apoptosis in cancer cells. Cancer Res. 2006;66:9270–80. PubMed
Gojo I, Zhang B, Fenton RG. The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1. Clin Cancer Res. 2002;8:3527–38. PubMed
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. Cancer Res. 2005;65:5399–407. PubMed
Raje N, Kumar S, Hideshima T, et al. Seliciclib (CYC202 or R-roscovitine), a small-molecule cyclin-dependent kinase inhibitor mediates activity via down-regulation of Mcl-1 in multiple myeloma. Blood. 2005;106:1042–7. PubMed PMC
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. Oncogene. 2010;29:2325–36. PubMed PMC
Krystof V, Chamrad I, Jorda R, Kohoutek J. Pharmacological targeting of CDK9 in cardiac hypertrophy. Med Res Rev. 2010;30:646–66. PubMed
Wang S, Fischer PM. Cyclin-dependent kinase 9: a key transcriptional regulator and potential drug target in oncology, virology and cardiology. Trends Pharmacol Sci. 2008;29:302–13. PubMed
Brown NR, Noble MEM, Endicott JA, Johnson LN. The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases. Nat Cell Biol. 1999;1:438–43. PubMed
Baumli S, Lolli G, Lowe ED, et al. The structure of P-TEFb (CDK9/cyclin T1) its complex with flavopiridol and regulation by phosphorylation. EMBO J. 2008;27:1907–18. PubMed PMC
Tahirov TH, Babayeva ND, Varzavand K, Cooper JJ, Sedore SC, Price DH. Crystal structure of HIV-1 Tat complexed with human P-TEFb. Nature. 2010;465:747–U2. PubMed PMC
Eswaran J, Knapp S. Insights into protein kinase regulation and inhibition by large scale structural comparison. Biochim Biophys Acta. 2010;1804:429–32. PubMed PMC
Bettayeb K, Baunbaek D, Delehouze C, et al. CDK Inhibitors Roscovitine and CR8 Trigger Mcl-1 Down-Regulation and Apoptotic Cell Death in Neuroblastoma Cells. Genes Cancer. 2010; 1:369–80. PubMed PMC
Baumli S, Endicott JA, Johnson LN. Halogen Bonds Form the Basis for Selective P-TEFb Inhibition by DRB. Chem Biol. 2010; 17:931–6. PubMed
de Azevedo WFJ, Mueller-Dieckmann HJ, Schulze-Gahmen U, Worland PJ, Sausville E, Kim SH. Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2 a cell cycle kinase. Proc Natl Acad Sci USA. 1996;93:2735–40. PubMed PMC
Bettayeb K, Oumata N, Echalier A, et al. CR8 a potent and selective, roscovitine-derived inhibitor of cyclin-dependent kinases. Oncogene. 2008;27:5797–807. PubMed
Vedadi M, Niesen FH, Allali-Hassani A, et al. Chemical screening methods to identify ligands that promote protein stability protein crystallization, and structure determination. Proc Natl Acad Sci USA. 2006;103:15835–40. PubMed PMC
Dickson MA, Schwartz GK. Development of cell-cycle inhibitors for cancer therapy. Curr Oncol. 2009;16:120–7. PubMed PMC
Carlson BA, Dubay MM, Sausville EA, Brizuela L, Worland PJ. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res. 1996;56:2973–8. PubMed
Squires MS, Feltell RE, Wallis NG, et al. Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol Cancer Ther . 2009;8:324–32. PubMed
Lam LT, Pickeral OK, Peng AC, et al. Genomic-scale measurement of mRNA turnover and the mechanisms of action of the anti-cancer drug flavopiridol. Genome Biol. 2001;2 RESEARCH0041. PubMed PMC
Chen R, Keating MJ, Gandhi V, Plunkett W. Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood. 2005;106:2513–9. PubMed PMC
Chen R, Wierda WG, Benaissa S, et al. Mechanism of Action of SNS-032 a Novel Cyclin Dependent Kinase Inhibitor in Chronic Lymphocytic Leukemia: Comparison with Flavopiridol. Blood . 2009;110:915A. PubMed PMC
Hahntow IN, Schneller F, Oelsner M, et al. Cyclin-dependent kinase inhibitor Roscovitine induces apoptosis in chronic lymphocytic leukemia cells. Leukemia. 2004;18:747–55. PubMed
Bettayeb K, Baunbaek D, Delehouze C, et al. CDK Inhibitors Roscovitine and CR8 Trigger Mcl-1 Down-Regulation and Apoptotic Cell Death in Neuroblastoma Cells. Genes Cancer. 2010; 1:369–80. PubMed PMC
Scrace SF, Kierstan P, Borgognoni J, et al. Transient treatment with CDK inhibitors eliminates proliferative potential even when their abilities to evoke apoptosis and DNA damage are blocked. Cell Cycle. 2008;7:3898–907. PubMed
Ambrosini G, Seelman SL, Qin LX, Schwartz GK. The cyclin-dependent kinase inhibitor flavopiridol potentiates the effects of topoisomerase I poisons by suppressing Rad51 expression in a p53- dependent manner. Cancer Res. 2008;68:2312–20. PubMed
Shah MA, Kortmansky J, Motwani M, et al. A phase I clinical trial of the sequential combination of irinotecan followed by flavopiridol. Clin Cancer Res. 2005;11:3836–45. PubMed
Mueller D, Bach C, Zeisig D, et al. A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood. 2007;110:4445–54. PubMed PMC
Frame S, Hogben M, Munro C, Blake DG, Green SR, Zheleva DI. Therapeutic potential of CDK inhibitors in MLL leukemias. Proceedings of the American Association for Cancer Research Annual Meeting; 2010 Apr 17-21; Washington, DC, USA. Amer Assoc Canc Res. 2010. p. 945.
Goh KC, Novotny-Diermayr V, Hart S, et al. TG02 a novel oral multi-kinase inhibitor of CDKs JAK2 and FLT3 with potent anti-leukemic properties. Leukemia. 2011. PubMed
Gordon V, Bhadel S, Wunderlich W, et al. CDK9 Regulates AR Promoter Selectivity and Cell Growth through Serine 81 Phosphorylation. Mol Endocrinol. 2010;24:2267–80. PubMed PMC
Ali MA, Choy H, Habib AA, Saha D. SNS-032 prevents tumor cell-induced angiogenesis by inhibiting vascular endothelial growth factor. Neoplasia. 2007;9:370–81. PubMed PMC
Melillo G, Sausville EA, Cloud K, Lahusen T, Varesio L, Senderowicz AM. Flavopiridol a protein kinase inhibitor down-regulates hypoxic induction of vascular endothelial growth factor expression in human monocytes. Cancer Res. 1999;59:5433–7. PubMed
Radhakrishnan SK, Gartel AL. A novel transcriptional inhibitor induces apoptosis in tumor cells and exhibits antiangiogenic activity. Cancer Res. 2006;66:3264–70. PubMed
Stockwin LH, Yu SX, Stotler H, Hollingshead MG, Newton DL. ARC (NSC 188491) has identical activity to Sangivamycin (NSC 65346) including inhibition of both P-TEFb and PKC. BMC Cancer. 2009;9:63. PubMed PMC
Liebl J, Weitensteiner SB, Vereb G, et al. Cyclin-dependent kinase 5 regulates endothelial cell migration and angiogenesis. J Biol Chem. 2010;285:35932–43. PubMed PMC
Krystof V, Cankar P, Frysova I, et al. 4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects. J Med Chem. 2006;49:6500–9. PubMed
Krystof V, Rarova L, Liebl J, et al. The selective P-TEFb inhibitor CAN508 targets angiogenesis. Eur J Med Chem. 2011;46:4289–94. PubMed
Ogba N, Doughman YQ, Chaplin LJ, et al. HEXIM1 modulates vascular endothelial growth factor expression and function in breast epithelial cells and mammary gland. Oncogene. 2010;29:3639–49. PubMed PMC
Zahler S, Liebl J, Furst R, Vollmar AM. Anti-angiogenic potential of small molecular inhibitors of cyclin dependent kinases in vitro. Angiogenesis. 2010;13:239–49. PubMed
Kohoutek J, Li QT, Blazek D, Luo ZP, Jiang HM, Peterlin BM. Cyclin T2 Is Essential for Mouse Embryogenesis. Mol Cell Biol . 2009;29:3280–5. PubMed PMC
Shim EY, Walker AK, Shi Y, Blackwell TK. CDK-9/cyclin T (PTEFb) is required in two postinitiation pathways for transcription in the C-elegans embryo. Genes Dev. 2002;16:2135–46. PubMed PMC
Eissenberg JC, Shilatifard A, Dorokhov N, Michener DE. Cdk9 is an essential kinase in Drosophila that is required for heat shock gene expression, histone methylation and elongation factor recruitment. Mol Genet Genomics. 2007;277:101–14. PubMed
Sekine C, Sugihara T, Miyake S, et al. Successful treatment of animal models of rheumatoid arthritis with small-molecule cyclindependent kinase inhibitors. Journal of Immunology. 2008;180:1954–61. PubMed
Schmerwitz UK, Sass G, Khandoga AG, et al. Flavopiridol Protects Against Inflammation by Attenuating Leukocyte- Endothelial Interaction via Inhibition of Cyclin-Dependent Kinase 9. Arterioscler Thromb Vasc Biol. 2011;31:280–U121. PubMed
Berberich N, Uhl B, Joore J, et al. Roscovitine blocks leukocyte extravasation by inhibition of cyclin-dependent kinases 5 and 9. Br J Pharmacol. 2011;163:1086–98. PubMed PMC
Arguello F, Alexander M, Sterry JA, et al. Flavopiridol induces apoptosis of normal lymphoid cells, causes immunosuppression and has potent antitumor activity in vivo against human leukemia and lymphoma xenografts. Blood. 1998;91:2482–90. PubMed
Herrmann CH, Carroll RG, Wei P, Jones KA, Rice AP. Tatassociated kinase TAK activity is regulated by distinct mechanisms in peripheral blood lymphocytes and promonocytic cell lines. J Virol. 1998;72:9881–8. PubMed PMC
Garriga J, Peng JM, Parreno M, Price DH, Henderson EE, Grana X. Upregulation of cyclin T1/CDK9 complexes during T cell activation. Oncogene. 1998;17:3093–102. PubMed
Ghose R, Liou LY, Herrmann CH, Rice AP. Induction of TAK (cyclin T1/P-TEFb) in purified resting CD4(+) T lymphocytes by combination of cytokines. J Virol. 2001;75:11336–43. PubMed PMC
Leucci E, De Falco G, Onnis A, et al. The role of the Cdk9/cyclin T1 complex in T cell differentiation. J Cell Physiol. 2007;212:411–5. PubMed
Ramakrishnan R, Dow EC, Rice AP. Characterization of Cdk9 T-loop phosphorylation in resting and activated CD4(+) T lymphocytes. J Leukoc Biol. 2009;86:1345–50. PubMed PMC
De Falco G, Leucci E, Onnis A, et al. Cdk9/Cyclin T1 complex: A key player during the activation/differentiation process of normal lymphoid B cells. J Cell Physiol. 2008;215:276–82. PubMed
Liou LY, Herrmann CH, Rice AP. Transient induction of cyclin T1 during human macrophage differentiation regulates human immunodeficiency virus type 1 Tat transactivation function. J Virol . 2002;76:10579–87. PubMed PMC
Smallie T, Ricchetti G, Horwood NJ, Feldmann M, Clark AR, Williams LM. IL-10 inhibits transcription elongation of the human TNF gene in primary macrophages. J Exp Med. 2010;207:2081–8. PubMed PMC
Haque A, Koide N, Iftakhar-E -Khuda, et al. Flavopiridol inhibits lipopolysaccharide-induced TNF-alpha production through inactivation of nuclear factor-kappa B and mitogen-activated protein kinases in the MyD88-dependent pathway. Microbiol Immunol. 2011;55:160–7. PubMed
Takada Y, Aggarwal BB. Flavopiridol inhibits NF-kappa B activation induced by various carcinogens and inflammatory agents through inhibition of I kappa B alpha kinase and p65 phosphorylation - Abrogation of cyclin D1 cyclooxygenase-2 and matrix metalloprotease-9. J Biol Chem. 2004;279:4750–9. PubMed
Nowak DE, Tian B, Jamaluddin M, et al. RelA Ser(276) phosphorylation is required for activation of a subset of NF-kappa B-dependent genes by recruiting cyclin-dependent kinase 9/cyclin T1 complexes. Mol Cell Biol. 2008;28:3623–38. PubMed PMC
Takada Y, Aggarwal BB. Flavopiridol inhibits NF-kappa B activation induced by various carcinogens and inflammatory agents through inhibition of I kappa B alpha kinase and p65 phosphorylation - Abrogation of cyclin D1 cyclooxygenase-2 and matrix metalloprotease-9. J Biol Chem. 2004;279:4750–9. PubMed
Huang B, Yang XD, Zhou MM, Ozato K, Chen LF. Brd4 Coactivates Transcriptional Activation of NF-kappa B via Specific Binding to Acetylated RelA. Mol Cell Biol. 2009;29:1375–87. PubMed PMC
Giraud S, Hurlstone A, Avril S, Coqueret O. Implication of BRG1 and cdk9 in the STAT3-mediated activation of the p21waf1 gene. Oncogene. 2004;23:7391–8. PubMed
Hou T, Ray S, Brasier AR. The functional role of an interleukin 6-inducible CDK9.STAT3 complex in human gamma-fibrinogen gene expression. J Biol Chem. 2007;282:37091–102. PubMed
MacLachlan TK, Sang NL, De Luca A, Puri PL, Levrero M, Giordano A. Binding of CDK9 to TRAF2. J Cell Biochem. 1998; 71:467–78. PubMed
De Falco G, Neri LM, De Falco M, et al. Cdk9 a member of the cdc2-like family of kinases, binds to gp130, the receptor of the IL-6 family of cytokines. Oncogene. 2002;21:7464–70. PubMed
CDK9 activity is critical for maintaining MDM4 overexpression in tumor cells