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Review Article

CDK9 as an Appealing Target for Therapeutic Interventions

Author(s): Shirin Eyvazi, Mohammad Saeid Hejazi, Homan Kahroba, Mozghan Abasi, Reza Eghdam Zamiri and Vahideh Tarhriz*

Volume 20, Issue 4, 2019

Page: [453 - 464] Pages: 12

DOI: 10.2174/1389450119666181026152221

Price: $65

Abstract

Cyclin Dependent Kinase 9 (CDK9) as a serine/threonine kinase belongs to a great number of CDKs. CDK9 is the main core of PTEF-b complex and phosphorylates RNA polymerase (RNAP) II besides other transcription factors which regulate gene transcription elongation in numerous physiological processes. Multi-functional nature of CDK9 in diverse cellular pathways proposes that it is as an appealing target. In this review, we summarized the recent findings on the molecular interaction of CDK9 with critical participant molecules to modulate their activity in various diseases. Furthermore, the presented review provides a rationale supporting the use of CDK9 as a therapeutic target in clinical developments for crucial diseases; particularly cancers will be reviewed.

Keywords: CDK9, cardiac pathway, cancer, viral agents, fibrosis, inflammation, RNAP.

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Graphical Abstract

[1]
Shore SM, Byers SA, Dent P, Price DH. Characterization of Cdk9 55 and differential regulation of two Cdk9 isoforms. Gene 2005; 350(1): 51-8.
[2]
Romano G, Giordano A. Role of the cyclin-dependent kinase 9-related pathway in mammalian gene expression and human diseases. Cell Cycle 2008; 7(23): 3664-8.
[3]
De Falco G, Bagella L, Claudio PP, et al. Physical interaction between CDK9 and B-Myb results in suppression of B-Myb gene autoregulation. Oncogene 2000; 19(3): 373.
[4]
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(49): 7464.
[5]
Eberhardy SR, Farnham PJ. c-Myc mediates activation of the cad promoter via a post-RNA polymerase II recruitment mechanism. J Biol Chem 2001; 276(51): 48562-71.
[6]
Gressel S, Schwalb B, Decker TM, et al. CDK9-dependent RNA polymerase II pausing controls transcription initiation. eLife 2017; 6: e29736.
[7]
Booth GT, Parua PK, Sanso M, Fisher RP, Lis JT. Cdk9 regulates a promoter-proximal checkpoint to modulate RNA Polymerase II elongation rate. bioRxiv 2017; 190512.
[8]
Parua PK, Booth GT, Sansó M, et al. A Cdk9–PP1 switch regulates the elongation–termination transition of RNA polymerase II. Nature 2018; 1.
[9]
Falco GD, Giordano A. CDK9: From basal transcription to cancer and AIDS. Cancer Biol Ther 2002; 1(4): 341-6.
[10]
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(1): 276-82.
[11]
Garriga J, Peng J, Parreño M, et al. Upregulation of cyclin T1/CDK9 complexes during T cell activation. Oncogene 1998; 17(24): 3093.
[12]
Sunagawa Y, Morimoto T, Takaya T, et al. Cyclin-dependent kinase-9 is a component of the p300/GATA4 complex required for phenylephrine-induced hypertrophy in cardiomyocytes. J Biol Chem 2010; 285(13): 9556-68.
[13]
Tarhriz V, Wagner KD, Masoumi Z, et al. CDK9 regulates apoptosis of myoblast cells by modulation of microRNA‐1 expression. J Cell Biochem 2018.
[14]
Marchesi I, Nieddu V, Caracciolo V, et al. Activation and function of murine Cyclin T2A and Cyclin T2B during skeletal muscle differentiation. J Cell Biochem 2013; 114(3): 728-34.
[15]
David SY, Zhao R, Hsu EL, et al. Cyclin‐dependent kinase 9-cyclin K functions in the replication stress response. EMBO Rep 2010; 11(11): 876-82.
[16]
Yu DS, Cortez D. A role for cdk9-cyclin k in maintaining genome integrity. Cell Cycle 2011; 10(1): 28-32.
[17]
Bacon CW, D’Orso I. CDK9: A Signaling hub for transcriptional control. Transcription 2018; 19: 1-19.
[18]
Gilmour J, Assi SA, Noailles L, et al. The Co-operation of RUNX1 with LDB1, CDK9 and BRD4 drives transcription factor complex relocation during haematopoietic specification. Sci Rep 2018; 8(1): 10410.
[19]
MacLachlan TK, Sang N, De Luca A, et al. Binding of CDK9 to TRAF2. J Cell Biochem 1998; 71(4): 467-78.
[20]
Egloff S, Studniarek C, Kiss T. 7SK small nuclear RNA, a multifunctional transcriptional regulatory RNA with gene-specific features. Transcription 2018; 9(2): 95-101.
[21]
C Quaresma AJ. Bugai A, Barboric M. Cracking the control of RNA polymerase II elongation by 7SK snRNP and P-TEFb. Nucleic Acids Res 2016; 44(16): 7527-39.
[22]
Nguyen VT, Kiss T, Michels AA, Bensaude O. 7SK small nuclear RNA binds to and inhibits the activity of CDK9/cyclin T complexes. Nature 2001; 414(6861): 322.
[23]
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(6861): 317.
[24]
Kusuhara M, Yamaguchi K, Nagasaki K, et al. Production of endothelin in human cancer cell lines. Cancer Res 1990; 50(11): 3257-61.
[25]
Kobbi L, Demey-Thomas E, Braye F, et al. An evolutionary conserved Hexim1 peptide binds to the Cdk9 catalytic site to inhibit P-TEFb. Proc Natl Acad Sci USA 2016; 113(45): 12721-6.
[26]
Barboric M, Peterlin BM. A new paradigm in eukaryotic biology: HIV Tat and the control of transcriptional elongation. PLoS Biol 2005; 3(2): e76.
[27]
Cho W-K, Zhou M, Jang MK, et al. Modulation of the Brd4/P-TEFb interaction by the human T-lymphotropic virus type 1 tax protein. J Virol 2007; 81(20): 11179-86.
[28]
Patel MC, Debrosse M, Smith M, et al. BRD4 coordinates recruitment of pause release factor P-TEFb and the pausing complex NELF/DSIF to regulate transcription elongation of interferon-stimulated genes. Mol Cell Biol 2013; 33(12): 2497-507.
[29]
Itzen F, Greifenberg AK, Bösken CA, Geyer M. Brd4 activates P-TEFb for RNA polymerase II CTD phosphorylation. Nucleic Acids Res 2014; 42(12): 7577-90.
[30]
Blank MF, Chen S, Poetz F. SIRT7-dependent deacetylation of CDK9 activates RNA polymerase II transcription. Nucleic Acids Res 2017; 45(5): 2675-86.
[31]
Ghanbarian H, Grandjean V, Cuzin F, Rassoulzadegan M. A network of regulations by small non-coding RNAs: The P-TEFb kinase in development and pathology. Front Genet 2011; 2: 95.
[32]
Kikuchi K, Hettmer S, Aslam MI, et al. Cell-cycle dependent expression of a translocation-mediated fusion oncogene mediates checkpoint adaptation in rhabdomyosarcoma. PLoS Genet 2014; 10(1): e1004107.
[33]
Xiao H, Xiao W, Cao J, et al. miR-206 functions as a novel cell cycle regulator and tumor suppressor in clear-cell renal cell carcinoma. Cancer Lett 2016; 374(1): 107-16.
[34]
Giacinti C, Chiandotto S, Tomei V, et al. The role of CDK9 in myogenesis. Ital J Anat Embryol 2014; 119(1): 1.
[35]
Chen J-F, Callis TE, Wang D-Z. microRNAs and muscle disorders. J Cell Sci 2009; 122(1): 13-20.
[36]
Weintraub H, Davis R, Tapscott S, et al. The myoD gene family: Nodal point during specification of the muscle cell lineage. Science 1991; 251(4995): 761-6.
[37]
Giacinti C, Musarò A, De Falco G, et al. Cdk9‐55: A new player in muscle regeneration. J Cell Physiol 2008; 216(3): 576-82.
[38]
Dey J, Deckwerth TL, Kerwin WS, Casalini JR, et al. Voruciclib, a clinical stage oral CDK9 inhibitor, represses MCL-1 and sensitizes high-risk Diffuse Large B-cell Lymphoma to BCL2 inhibition. Sci Rep 2017; 7(1): 18007.
[39]
Cowling VH, Cole MD, Eds. editors Mechanism of transcriptional activation by the Myc oncoproteins Seminars in cancer biology; 2006 Elsevier.
[40]
Gargano B, Amente S, Majello B, Lania L. P-TEFb is a crucial co-factor for Myc transactivation. Cell Cycle 2007; 6(16): 2031-7.
[41]
Chen H, Liu H, Qing G. Targeting oncogenic Myc as a strategy for cancer treatment. Signal Transduct Target Ther 2018; 3(1): 5.
[42]
de Alboran IM, O’Hagan RC, Gärtner F, et al. Analysis of C-MYC function in normal cells via conditional gene-targeted mutation. Immunity 2001; 14(1): 45-55.
[43]
Schlosser I. HoÈlzel M, Mürnseer M, et al. A role for c‐Myc in the regulation of ribosomal RNA processing. Nucleic Acids Res 2003; 31(21): 6148-56.
[44]
Russo P, Arzani D, Trombino S, Falugi C. c-myc down-regulation induces apoptosis in human cancer cell lines exposed to RPR-115135 (C31H29NO4), a non-peptidomimetic farnesyltransferase inhibitor. J Pharmacol Exp Ther 2003; 304(1): 37-47.
[45]
Clavería C, Giovinazzo G, Sierra R, Torres M. Myc-driven endogenous cell competition in the early mammalian embryo. Nature 2013; 500(7460): 39.
[46]
Gandarillas A, Watt FM. c-Myc promotes differentiation of human epidermal stem cells. Genes Develep 1997; 11(21): 2869-82.
[47]
Bellan C, De Falco G, Lazzi S, et al. CDK9/CYCLIN T1 expression during normal lymphoid differentiation and malignant transformation. J Pathol 2004; 203(4): 946-52.
[48]
Franco LC, Morales F, Boffo S, Giordano A. CDK9: A key player in cancer and other diseases. J Cell Biochem 2018; 119(2): 1273-84.
[49]
Kretz A-L, Schaum M, Richter J, et al. CDK9 is a prognostic marker and therapeutic target in pancreatic cancer. Tumour Biol 2017; 39(2): 1010428317694304.
[50]
Grana X, De Luca A, Sang N, et al. PITALRE, a nuclear CDC2-related protein kinase that phosphorylates the retinoblastoma protein in vitro. Proc Natl Acad Sci USA 1994; 91(9): 3834-8.
[51]
Sun A, Bagella L, Tutton S, Romano G, Giordano A. From G0 to S phase: A view of the roles played by the retinoblastoma (Rb) family members in the Rb‐E2F pathway. J Cell Biochem 2007; 102(6): 1400-4.
[52]
Shao Z, Robbins PD. Differential regulation of E2F and Sp1-mediated transcription by G1 cyclins. Oncogene 1995; 10(2): 221-8.
[53]
Simone C, Bagella L, Bellan C, Giordano A. Physical interaction between pRb and cdk9/cyclinT2 complex. Oncogene 2002; 4158.
[54]
Tong Z, Chatterjee D, Deng D, et al. Antitumor effects of cyclin dependent kinase 9 inhibition in esophageal adenocarcinoma. Oncotarget 2017; 8(17): 28696.
[55]
Veeranki OLM, Dokey R, Mejia A, et al. Role of CDK9 inhibition as a sensitizer to radiation in esophageal adenocarcinoma: In vitro and in vivo efficacy study. AACR 2017.
[56]
Marchesi I. A novel role of Cdk9/CyclinT2 complexes in skeletal muscle and rhabdomyosarcoma cells 2010.
[57]
Biswas S, Rao CM. Epigenetics in cancer: Fundamentals and beyond. Pharmacol Ther 2017; 173: 118-34.
[58]
Zhang H, Pandey S, Travers M, et al. Targeting CDK9 reactivates epigenetically silenced genes in cancer. AACR. Cell 2018; 175(5): 1244-58.e26.
[59]
Pierre RS, Kadoch C. Mammalian SWI/SNF complexes in cancer: Emerging therapeutic opportunities. Curr Opin Genet Dev 2017; 42: 56-67.
[60]
Lam F, Abbas AY, Shao H, et al. Targeting RNA transcription and translation in ovarian cancer cells with pharmacological inhibitor CDKI-73. Oncotarget 2014; 5(17): 7691.
[61]
Lineham E, Spencer J, Morley SJ. Dual abrogation of MNK and mTOR: a novel therapeutic approach for the treatment of aggressive cancers. Future Med Chem 2017; 9(13): 1539-55.
[62]
Sonawane YA, Taylor MA, Napoleon JV, et al. Cyclin dependent kinase 9 inhibitors for cancer therapy: Miniperspective. J Med Chem 2016; 59(19): 8667-84.
[63]
Kim JB, Sharp PA. Positive transcription elongation factor B phosphorylates hSPT5 and RNA polymerase II carboxyl-terminal domain independently of cyclin-dependent kinase-activating kinase. J Biol Chem 2001; 276(15): 12317-23.
[64]
Ping Y-H, Rana TM. DSIF and NELF interact with RNA polymerase II elongation complex and HIV-1 Tat stimulates P-TEFb-mediated phosphorylation of RNA polymerase II and DSIF during transcription elongation. J Biol Chem 2001; 276(16): 12951-8.
[65]
Yang X, Herrmann CH, Rice AP. The human immunodeficiency virus Tat proteins specifically associate with TAK in vivo and require the carboxyl-terminal domain of RNA polymerase II for function. J Virol 1996; 70(7): 4576-84.
[66]
Zhu Y, Pe’ery T, Peng J, et al. Transcription elongation factor P-TEFb is required for HIV-1 tat transactivation in vitro. Genes Dev 1997; 11(20): 2622-32.
[67]
Mancebo HS, Lee G, Flygare J, et al. P-TEFb kinase is required for HIV Tat transcriptional activation in vivo and in vitro. Genes Dev 1997; 11(20): 2633-44.
[68]
Kwak YT, Ivanov D, Guo J, Nee E, Gaynor RB. Role of the human and murine cyclin T proteins in regulating HIV-1 tat-activation. J Mole Ziol 1999; 288(1): 57-69.
[69]
Fujinaga K, Taube R, Wimmer J, Cujec TP, Peterlin BM. Interactions between human cyclin T, Tat, and the transactivation response element (TAR) are disrupted by a cysteine to tyrosine substitution found in mouse cyclin T. Proceedings National Acad Sci USA 1999; 96(4): 1285-90.
[70]
Yamaguchi Y, Takagi T, Wada T, et al. NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell 1999; 97(1): 41-51.
[71]
Booth GT, Parua PK, Sansó M, Fisher RP, Lis JT. Cdk9 regulates a promoter-proximal checkpoint to modulate RNA polymerase II elongation rate in fission yeast. Nat Commun 2018; 9(1): 543.
[72]
Bagashev A, Fan S, Mukerjee R, et al. Cdk9 phosphorylates Pirh2 protein and prevents degradation of p53 protein. Cell Cycle 2013; 12(10): 1569-77.
[73]
Castrogiovanni C, Waterschoot B, De Backer O, Dumont P. Serine 392 phosphorylation modulates p53 mitochondrial translocation and transcription-independent apoptosis. Cell Death Differ 2018; 25(1): 190.
[74]
O’Brien SK, Cao H, Nathans R, Ali A, Rana TM. P-TEFb kinase complex phosphorylates histone H1 to regulate expression of cellular and HIV-1 genes. J Biol Chem 2010; 285(39): 29713-20.
[75]
Chun T-W, Engel D, Mizell SB, Ehler LA, Fauci AS. Induction of HIV-1 replication in latently infected CD4+ T cells using a combination of cytokines. J Exp Med 1998; 188(1): 83-91.
[76]
Amini S, Clavo A, Nadraga Y, et al. Interplay between cdk9 and NF-κB factors determines the level of HIV-1 gene transcription in astrocytic cells. Oncogene 2002; 21(37): 5797.
[77]
Vijayalingam S, Chinnadurai G. Adenovirus L-E1A activates transcription through mediator complex-dependent recruitment of the super elongation complex. J Virol 2013; 87(6): 3425-34.
[78]
Prasad V, Suomalainen M, Hemmi S, Greber UF. Cell cycle-dependent kinase Cdk9 is a postexposure drug target against human adenoviruses. ACS Infect Dis 2017; 3(6): 398-405.
[79]
Bark-Jones S, Webb H, West M. EBV EBNA 2 stimulates CDK9-dependent transcription and RNA polymerase II phosphorylation on serine 5. Oncogene 2006; 25(12): 1775.
[80]
Bazarbachi A. CDK9 inhibition for ATL therapy. Blood 2017; 130(9): 1074-5.
[81]
Kapasi AJ, Clark CL, Tran K, Spector DH. 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; 83(11): 5904-17.
[82]
Zaborowska J, Isa NF, Murphy S. P‐TEFb goes viral. BioEssays 2016; 38(S1)
[83]
Guo L, Wu W-j, Liu L-d, et al. Herpes simplex virus 1 ICP22 inhibits the transcription of viral gene promoters by binding to and blocking the recruitment of P-TEFb. PLoS One 2012; 7(9): e45749.
[84]
Zhao Z, Tang K-W, Muylaert I, Samuelsson T, Elias P. Cdk9 and Spt5 are specifically required for expression of Herpes simplex virus 1 replication-dependent late genes. J Biol Chem 2017: jbc. M117. 806000.
[85]
Kadaja M, Silla T, Ustav E, Ustav M. Papillomavirus DNA replication-from initiation to genomic instability. Virol 2009; 384(2): 360-8.
[86]
Sumi E, Nomura T, Asada R, et al. Safety and plasma concentrations of a Cyclin-Dependent Kinase 9 (CDK9) inhibitor, fit039, administered by a single adhesive skin patch applied on normal skin and cutaneous warts. Clin Drug Invest 2018; pp. 1-7.
[87]
Ajiro M, Sakai H, Onogi H, et al. CDK9 inhibitor fit-039 suppresses viral oncogenes E6 and E7 and has a therapeutic effect on HPV-induced neoplasia. Clin Cancer Res 2018; 24(18): 4518-28.
[88]
Zhang J, Li G, Ye X. Cyclin T1/CDK9 interacts with influenza A virus polymerase and facilitates its association with cellular RNA polymerase II. J Virol 2010; 84(24): 12619-27.
[89]
Li Ll, Hu ST, Wang SH, et al. Positive Transcription Elongation Factor b (P‐TEFb) contributes to dengue virus‐stimulated induction of interleukin‐8 (IL‐8). Cell Microbiol 2010; 12(11): 1589-603.
[90]
Chang P-C, Li M. Kaposi’s sarcoma-associated herpesvirus K-cyclin interacts with Cdk9 and stimulates Cdk9-mediated phosphorylation of p53 tumor suppressor. J Virol 2008; 82(1): 278-90.
[91]
Tian B, Zhao Y, Sun H, et al. BRD4 mediates NF-κB-dependent epithelial-mesenchymal transition and pulmonary fibrosis via transcriptional elongation. Am J Physiol Lung Cell Mol Physiol 2016; 311(6): L1183-201.
[92]
Ijaz T, Tilton RG, Brasier AR. Cytokine amplification and macrophage effector functions in aortic inflammation and abdominal aortic aneurysm formation. J Thorac Dis 2016; 8(8): E746.
[93]
Bagella L, MacLachlan TK, Buono RJ, et al. Cloning of murine CDK9/PITALRE and its tissue‐specific expression in development. J Cell Physiol 1998; 177(2): 206-13.
[94]
Hou T, Ray S, Brasier AR. The functional role of an interleukin 6-inducible CDK9· STAT3 complex in human γ-fibrinogen gene expression. J Biol Chem 2007; 282(51): 37091-102.
[95]
Vomero M, Barbati C, Colasanti T, et al. Autophagy and rheumatoid arthritis: Current knowledges and future perspectives. Front Immunol 2018; •••: 9.
[96]
Hellvard A, Zeitlmann L, Heiser U, et al. Inhibition of CDK9 as a therapeutic strategy for inflammatory arthritis. Sci Rep 2016; 6: 31441.
[97]
Kourtzelis I, Kotlabova K, Lim J-H, et al. Developmental endothelial locus-1 modulates platelet-monocyte interactions and instant blood-mediated inflammatory reaction in islet transplantation. Thromb Haemost 2016; 115(4): 781.
[98]
Boffo S, Damato A, Alfano L, Giordano A. CDK9 inhibitors in acute myeloid leukemia. J Exp Clin Cancer Res 2018; 37(1): 36.
[99]
Morales F, Giordano A. Overview of CDK9 as a target in cancer research. Cell Cycle 2016; 15(4): 519-27.
[100]
Romano G. Deregulations in the cyclin-dependent kinase-9-related pathway in cancer: Implications for drug discovery and development. ISRN Oncol 2013; 2013.
[101]
Kumar SK, LaPlant B, Chng WJ, et al. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood 2015; 125(3): 443-8.
[102]
Fu W, Ma L, Chu B, et al. The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells. Mol Cancer Therap 2011: Molcanther. 0167.2011.
[103]
Chen Z, Wang Z, Pang JC, et al. Multiple CDK inhibitor dinaciclib suppresses neuroblastoma growth via inhibiting CDK2 and CDK9 activity. Sci Rep 2016; 6: 29090.
[104]
Baker A, Gregory GP, Verbrugge I, et al. The CDK9 inhibitor dinaciclib exerts potent apoptotic and antitumor effects in preclinical models of MLL-rearranged acute myeloid leukemia. Cancer Res 2016; 76(5): 1158-69.
[105]
Baumann K, Kim H, Rinke J, Plaum T, Wagner U, Reinartz S. Effects of alvocidib and carboplatin on ovarian cancer cells in vitro. Experimental oncology. 2013(35,№ 3):168-73.
[106]
Mariaule G, Belmont P. Cyclin-dependent kinase inhibitors as marketed anticancer drugs: where are we now? A short survey. Mol 2014; 19(9): 14366-82.
[107]
Brägelmann J, Dammert MA, Dietlein F, et al. Systematic kinase inhibitor profiling identifies CDK9 as a synthetic lethal target in NUT midline carcinoma. Cell Reports 2017; 20(12): 2833-45.
[108]
Byth KF, Thomas A, Hughes G, et al. AZD5438, a potent oral inhibitor of cyclin-dependent kinases 1, 2, and 9, leads to pharmacodynamic changes and potent antitumor effects in human tumor xenografts. Mol Cancer Ther 2009; 8(7): 1856-66.
[109]
Boss DS, Schwartz GK, Middleton MR, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours. Ann Oncol 2009; 21(4): 884-94.
[110]
Cirstea D, Hideshima T, Santo L, et al. Small-molecule multi-targeted kinase inhibitor RGB-286638 triggers P53-dependent and-independent anti-multiple myeloma activity through inhibition of transcriptional CDKs. Leukemia 2013; 27(12): 2366.
[111]
Siemeister G, Luecking U, Wagner C, et al. Molecular and pharmacodynamic characteristics of the novel multi-target tumor growth inhibitor ZK 304709. Biomed Pharmacother 2006; 60(6): 269-72.
[112]
Hofmeister CC, Berdeja JG, Vesole DH, Suvannasankha A, Parrott T, Abonour R. TG02, an oral CDK9-inhibitor, in combination with carfilzomib demonstrated objective responses in carfilzomib refractory multiple myeloma patients. Am Soc Hematol 2015.
[113]
Yin T, Lallena MJ, Kreklau EL, et al. A novel CDK9 inhibitor shows potent antitumor efficacy in preclinical hematologic tumor models. Mol Cancer Ther 2014; 13(6): 1442-56.
[114]
Mohapatra S, Coppola D, Riker AI, Pledger WJ. Roscovitine inhibits differentiation and invasion in a three-dimensional skin reconstruction model of metastatic melanoma. Mol Cancer Res 2007; 5(2): 145-51.
[115]
Joshi KS, Rathos MJ, Mahajan P, et al. P276-00, a novel cyclin-dependent inhibitor induces G1-G2 arrest, shows antitumor activity on cisplatin-resistant cells and significant in vivo efficacy in tumor models. Mol Cancer Ther 2007; 6(3): 926-34.
[116]
Xie S, Jiang H, Zhai X-w, et al. Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells. Acta Pharmacol Sin 2016; 37(11): 1481.
[117]
Alzani R, Pedrini O, Albanese C, et al. Therapeutic efficacy of the pan-cdk inhibitor PHA-793887 in vitro and in vivo in engraftment and high-burden leukemia models. Experimental hematology. 2010;38(4):259-69. e2.
[118]
Yecies D, Carlson NE, Deng J, Letai A. Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1. Blood 2010; 115(16): 3304-13.
[119]
Albert T, Rigault C, Eickhoff J, et al. Characterization of molecular and cellular functions of the cyclin‐dependent kinase CDK9 using a novel specific inhibitor. Br J Pharmacol 2014; 171(1): 55-68.
[120]
Lücking U, Scholz A, Lienau P, et al. Identification of atuveciclib (BAY 1143572), the first highly selective, clinical PTEFb/CDK9 inhibitor for the treatment of cancer. ChemMedChem 2017; 12(21): 1776-93.
[121]
Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov 2009; 8(7): 547.
[122]
Bettayeb K, Sallam H, Ferandin Y, et al. N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine. Mol Cancer Ther 2008; 7(9): 2713-24.
[123]
Tanaka T, Okuyama-Dobashi K, Murakami S, et al. Inhibitory effect of CDK9 inhibitor FIT-039 on hepatitis B virus propagation. Antiviral Res 2016; 133: 156-64.

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