An Overview of CDK Enzyme Inhibitors in Cancer Therapy

doi:10.2174/1568009623666230320144713
摘要

在癌症治疗中处理细胞周期的能力带来了新的药物开发的可能性。周期蛋白依赖性激酶是一组控制细胞周期进程的蛋白质。当特定CDK位点被磷酸化时，CDK/细胞周期蛋白复合物被激活。由于它们的非选择性和严重的毒性，大多数第一代CDK抑制剂(也称为泛CDK抑制剂)尚未被批准用于临床。尽管如此，在允许泛cdk抑制剂在临床环境中使用方面已经取得了重大进展。近年来，由于联合治疗技术的引入，泛cdk抑制剂的毒副作用已经降低。因此，泛cdk抑制剂作为一种联合治疗方法重新获得了许多临床潜力。本文介绍了CDK家族成员，并讨论了它们在细胞周期控制中的重要作用。然后，我们描述了CDK抑制剂的研究现状，重点是CDK4/6以外的抑制剂。我们根据第一代泛CDKIs的研究阶段、临床试验和肿瘤靶向性，分别提到了黄吡醇和罗斯科维汀，以及第二代泛CDKIs的dinaciclib、P276-00、AT7519、TG02、roniclib和RGB-286638。CDKIs是CDK4/6、CDK7、CDK9和CDK12抑制剂。最后，我们研究了CDK抑制剂和PD1/PDL1抗体一起使用时的疗效，这可能会导致一种可行的癌症治疗策略的发展。
关键词: 细胞周期蛋白，CDK，基因表达，细胞周期调控，癌症，抑制。
« Previous Next »
图形摘要

[1]
Garrett, M.D.; Fattaey, A. CDK inhibition and cancer therapy. Curr. Opin. Genet. Dev.,  1999, 9(1), 104-111.
 [http://dx.doi.org/10.1016/S0959-437X(99)80015-X] [PMID:  10072351]

[2]
Arellano, M.; Moreno, S. Regulation of CDK/cyclin complexes during the cell cycle. Int. J. Biochem. Cell Biol.,  1997, 29(4), 559-573.
 [http://dx.doi.org/10.1016/S1357-2725(96)00178-1] [PMID:  9363633]

[3]
Patel, V.; Senderowicz, A.M.; Pinto, D., Jr; Igishi, T.; Raffeld, M.; Quintanilla-Martinez, L.; Ensley, J.F.; Sausville, E.A.; Gutkind, J.S. Flavopiridol, a novel cyclin-dependent kinase inhibitor, suppresses the growth of head and neck squamous cell carcinomas by inducing apoptosis. J. Clin. Invest.,  1998, 102(9), 1674-1681.
 [http://dx.doi.org/10.1172/JCI3661] [PMID:  9802881]

[4]
Aklilu, M.; Kindler, H.L.; Donehower, R.C.; Mani, S.; Vokes, E.E. Phase II study of flavopiridol in patients with advanced colorectal cancer. Ann. Oncol.,  2003, 14(8), 1270-1273.
 [http://dx.doi.org/10.1093/annonc/mdg343] [PMID:  12881391]

[5]
Olgen, S. Overview on anticancer drug design and development. Curr. Med. Chem.,  2018, 25(15), 1704-1719.
 [http://dx.doi.org/10.2174/0929867325666171129215610] [PMID:  29189124]

[6]
Ivanchuk, S.M.; Rutka, J.T. Regulation of the cell cycle and interventional developmental therapeutics. In:  Handbook of brain tumor chemotherapy; Academic Press, 2006; pp. 123-140.
 [http://dx.doi.org/10.1016/B978-012088410-0/50047-0]

[7]
Whalen, K. Lippincott® Illustrated Reviews: Pharmacology; Wolters Kluwer: India, 2018. 

[8]
Malumbres, M.; Barbacid, M. Mammalian cyclin-dependent kinases. Trends Biochem. Sci.,  2005, 30(11), 630-641.
 [http://dx.doi.org/10.1016/j.tibs.2005.09.005] [PMID:  16236519]

[9]
Colas, P.; Cohen, B.; Jessen, T.; Grishina, I.; McCoy, J.; Brent, R. Genetic selection of peptide aptamers that recognize and inhibit cyclin-dependent kinase 2. Nature,  1996, 380(6574), 548-550.
 [http://dx.doi.org/10.1038/380548a0] [PMID:  8606778]

[10]
Johnson, N.; Shapiro, G.I. Cyclin-dependent kinase 4/6 inhibition in cancer therapy. Cell Cycle,  2012, 11(21), 3913.
 [http://dx.doi.org/10.4161/cc.22390] [PMID:  23032266]

[11]
Mayer, E.L. Targeting breast cancer with CDK inhibitors. Curr. Oncol. Rep.,  2015, 17(5), 20.
 [http://dx.doi.org/10.1007/s11912-015-0443-3] [PMID:  25716100]

[12]
Bergqvist, J.; Elmberger, G.; Ohd, J.; Linderholm, B.; Bjohle, J.; Hellborg, H.; Nordgren, H.; Borg, A.L.; Skoog, L.; Bergh, J. Activated ERK1/2 and phosphorylated oestrogen receptor α are associated with improved breast cancer survival in women treated with tamoxifen. Eur. J. Cancer,  2006, 42(8), 1104-1112.
 [http://dx.doi.org/10.1016/j.ejca.2006.01.028] [PMID:  16603346]

[13]
Park, D.S.; Levine, B.; Ferrari, G.; Greene, L.A. Cyclin dependent kinase inhibitors and dominant negative cyclin dependent kinase 4 and 6 promote survival of NGF-deprived sympathetic neurons. J. Neurosci.,  1997, 17(23), 8975-8983.
 [http://dx.doi.org/10.1523/JNEUROSCI.17-23-08975.1997] [PMID:  9364045]

[14]
Peyressatre, M.; Prével, C.; Pellerano, M.; Morris, M. Targeting cyclin-dependent kinases in human cancers: From small molecules to Peptide inhibitors. Cancers,  2015, 7(1), 179-237.
 [http://dx.doi.org/10.3390/cancers7010179] [PMID:  25625291]

[15]
Malumbres, M. Cyclin-dependent kinases. Genome Biol.,  2014, 15(6), 122.
 [http://dx.doi.org/10.1186/gb4184] [PMID:  25180339]

[16]
Knockaert, M.; Greengard, P.; Meijer, L. Pharmacological inhibitors of cyclin-dependent kinases. Trends Pharmacol. Sci.,  2002, 23(9), 417-425.
 [http://dx.doi.org/10.1016/S0165-6147(02)02071-0] [PMID:  12237154]

[17]
Pines, J. Cyclins and cyclin-dependent kinases: A biochemical view. Biochem. J.,  1995, 308(3), 697-711.
 [http://dx.doi.org/10.1042/bj3080697] [PMID:  8948422]

[18]
Sánchez-Martínez, C.; Gelbert, L.M.; Lallena, M.J.; de Dios, A. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs. Bioorg. Med. Chem. Lett.,  2015, 25(17), 3420-3435.
 [http://dx.doi.org/10.1016/j.bmcl.2015.05.100] [PMID:  26115571]

[19]
Fry, D.W.; Harvey, P.J.; Keller, P.R.; Elliott, W.L.; Meade, M.; Trachet, E.; Albassam, M.; Zheng, X.; Leopold, W.R.; Pryer, N.K.; Toogood, P.L. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol. Cancer Ther.,  2004, 3(11), 1427-1438.
 [http://dx.doi.org/10.1158/1535-7163.1427.3.11] [PMID:  15542782]

[20]
Spring, L.M.; Wander, S.A.; Zangardi, M.; Bardia, A. CDK 4/6 inhibitors in breast cancer: Current controversies and future directions. Curr. Oncol. Rep.,  2019, 21(3), 25.
 [http://dx.doi.org/10.1007/s11912-019-0769-3] [PMID:  30806829]

[21]
Long, F.; He, Y.; Fu, H.; Li, Y.; Bao, X.; Wang, Q.; Wang, Y.; Xie, C.; Lou, L. Preclinical characterization of SHR6390, a novel CDK 4/6 inhibitor, in vitro and in human tumor xenograft models. Cancer Sci.,  2019, 110(4), 1420-1430.
 [http://dx.doi.org/10.1111/cas.13957] [PMID:  30724426]

[22]
Besson, A.; Dowdy, S.F.; Roberts, J.M. CDK inhibitors: Cell cycle regulators and beyond. Dev. Cell,  2008, 14(2), 159-169.
 [http://dx.doi.org/10.1016/j.devcel.2008.01.013] [PMID:  18267085]

[23]
Malumbres, M.; Pevarello, P.; Barbacid, M.; Bischoff, J.R. CDK inhibitors in cancer therapy: what is next? Trends Pharmacol. Sci.,  2008, 29(1), 16-21.
 [http://dx.doi.org/10.1016/j.tips.2007.10.012] [PMID:  18054800]

[24]
Senderowicz, A.M. Small-molecule cyclin-dependent kinase modulators. Oncogene,  2003, 22(42), 6609-6620.
 [http://dx.doi.org/10.1038/sj.onc.1206954] [PMID:  14528286]

[25]
Schwartz, G.K. CDK inhibitors: Cell cycle arrest versus apoptosis. Cell Cycle,  2002, 1(2), 113-114.
 [http://dx.doi.org/10.4161/cc.1.2.112] [PMID:  12429920]

[26]
Arris, C.E.; Boyle, F.T.; Calvert, A.H.; Curtin, N.J.; Endicott, J.A.; Garman, E.F.; Gibson, A.E.; Golding, B.T.; Grant, S.; Griffin, R.J.; Jewsbury, P.; Johnson, L.N.; Lawrie, A.M.; Newell, D.R.; Noble, M.E.M.; Sausville, E.A.; Schultz, R.; Yu, W. Identification of novel purine and pyrimidine cyclin-dependent kinase inhibitors with distinct molecular interactions and tumor cell growth inhibition profiles. J. Med. Chem.,  2000, 43(15), 2797-2804.
 [http://dx.doi.org/10.1021/jm990628o] [PMID:  10956187]

[27]
Berkofsky-Fessler, W.; Nguyen, T.Q.; Delmar, P.; Molnos, J.; Kanwal, C.; DePinto, W.; Rosinski, J.; McLoughlin, P.; Ritland, S.; DeMario, M.; Tobon, K.; Reidhaar-Olson, J.F.; Rueger, R.; Hilton, H. Preclinical biomarkers for a cyclin-dependent kinase inhibitor translate to candidate pharmacodynamic biomarkers in phase I patients. Mol. Cancer Ther.,  2009, 8(9), 2517-2525.
 [http://dx.doi.org/10.1158/1535-7163.MCT-09-0083] [PMID:  19755512]

[28]
Cicenas, J.; Valius, M. The CDK inhibitors in cancer research and therapy. J. Cancer Res. Clin. Oncol.,  2011, 137(10), 1409-1418.
 [http://dx.doi.org/10.1007/s00432-011-1039-4] [PMID:  21877198]

[29]
Zhang, M.; Zhang, L.; Hei, R.; Li, X.; Cai, H.; Wu, X.; Zheng, Q.; Cai, C. CDK inhibitors in cancer therapy, an overview of recent development. Am. J. Cancer Res.,  2021, 11(5), 1913-1935.
 [PMID:  34094661]

[30]
Meijer, L.; Borgne, A.; Mulner, O.; Chong, J.P.J.; Blow, J.J.; Inagaki, N.; Inagaki, M.; Delcros, J.G.; Moulinoux, J.P. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur. J. Biochem.,  1997, 243(1-2), 527-536.
 [http://dx.doi.org/10.1111/j.1432-1033.1997.t01-2-00527.x] [PMID:  9030781]

[31]
Cicenas, J.; Kalyan, K.; Sorokinas, A.; Stankunas, E.; Levy, J.; Meskinyte, I.; Stankevicius, V.; Kaupinis, A.; Valius, M. Roscovitine in cancer and other diseases. Ann. Transl. Med.,  2015, 3(10), 135.
 [http://dx.doi.org/10.3978/j.issn.2305-5839.2015.03.61] [PMID:  26207228]

[32]
Whittaker, S.R.; Mallinger, A.; Workman, P.; Clarke, P.A. Inhibitors of cyclin-dependent kinases as cancer therapeutics. Pharmacol. Ther.,  2017, 173, 83-105.
 [http://dx.doi.org/10.1016/j.pharmthera.2017.02.008] [PMID:  28174091]

[33]
Asghar, U.; Witkiewicz, A.K.; Turner, N.C.; Knudsen, E.S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov.,  2015, 14(2), 130-146.
 [http://dx.doi.org/10.1038/nrd4504] [PMID:  25633797]

[34]
Zeidner, J.F.; Karp, J.E. Clinical activity of alvocidib (flavopiridol) in acute myeloid leukemia. Leuk. Res.,  2015, 39(12), 1312-1318.
 [http://dx.doi.org/10.1016/j.leukres.2015.10.010] [PMID:  26521988]

[35]
Parker, B.W.; Kaur, G.; Nieves-Neira, W.; Taimi, M.; Kohlhagen, G.; Shimizu, T.; Losiewicz, M.D.; Pommier, Y.; Sausville, E.A.; Senderowicz, A.M. Early induction of apoptosis in hematopoietic cell lines after exposure to flavopiridol. Blood,  1998, 91(2), 458-465.
 [http://dx.doi.org/10.1182/blood.V91.2.458] [PMID:  9427698]

[36]
Phelps, M.A.; Lin, T.S.; Johnson, A.J.; Hurh, E.; Rozewski, D.M.; Farley, K.L.; Wu, D.; Blum, K.A.; Fischer, B.; Mitchell, S.M.; Moran, M.E.; Brooker-McEldowney, M.; Heerema, N.A.; Jarjoura, D.; Schaaf, L.J.; Byrd, J.C.; Grever, M.R.; Dalton, J.T. Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia. Blood,  2009, 113(12), 2637-2645.
 [http://dx.doi.org/10.1182/blood-2008-07-168583] [PMID:  18981292]

[37]
Lin, T.S.; Ruppert, A.S.; Johnson, A.J.; Fischer, B.; Heerema, N.A.; Andritsos, L.A.; Blum, K.A.; Flynn, J.M.; Jones, J.A.; Hu, W.; Moran, M.E.; Mitchell, S.M.; Smith, L.L.; Wagner, A.J.; Raymond, C.A.; Schaaf, L.J.; Phelps, M.A.; Villalona-Calero, M.A.; Grever, M.R.; Byrd, J.C. Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J. Clin. Oncol.,  2009, 27(35), 6012-6018.
 [http://dx.doi.org/10.1200/JCO.2009.22.6944] [PMID:  19826119]

[38]
Bose, P.; Simmons, G.L.; Grant, S. Cyclin-dependent kinase inhibitor therapy for hematologic malignancies. Expert Opin. Investig. Drugs,  2013, 22(6), 723-738.
 [http://dx.doi.org/10.1517/13543784.2013.789859] [PMID:  23647051]

[39]
Karp, J.E.; Blackford, A.; Smith, B.D.; Alino, K.; Seung, A.H.; Bolaños-Meade, J.; Greer, J.M.; Carraway, H.E.; Gore, S.D.; Jones, R.J.; Levis, M.J.; McDevitt, M.A.; Doyle, L.A.; Wright, J.J. Clinical activity of sequential flavopiridol, cytosine arabinoside, and mitoxantrone for adults with newly diagnosed, poor-risk acute myelogenous leukemia. Leuk. Res.,  2010, 34(7), 877-882.
 [http://dx.doi.org/10.1016/j.leukres.2009.11.007] [PMID:  19962759]

[40]
Baker, A.; Gregory, G.P.; Verbrugge, I.; Kats, L.; Hilton, J.J.; Vidacs, E.; Lee, E.M.; Lock, R.B.; Zuber, J.; Shortt, J.; Johnstone, R.W. The CDK9 inhibitor dinaciclib exerts potent apoptotic and antitumor effects in preclinical models of MLL-rearranged acute myeloid leukemia. Cancer Res.,  2016, 76(5), 1158-1169.
 [http://dx.doi.org/10.1158/0008-5472.CAN-15-1070] [PMID:  26627013]

[41]
Johnson, A.J.; Yeh, Y-Y.; Smith, L.L.; Wagner, A.J.; Hessler, J.; Gupta, S.; Flynn, J.; Jones, J.; Zhang, X.; Bannerji, R.; Grever, M.R.; Byrd, J.C. The novel cyclin-dependent kinase inhibitor dinaciclib (SCH727965) promotes apoptosis and abrogates microenvironmental cytokine protection in chronic lymphocytic leukemia cells. Leukemia,  2012, 26(12), 2554-2557.
 [http://dx.doi.org/10.1038/leu.2012.144] [PMID:  22791353]

[42]
Hossain, D.M.S.; Javaid, S.; Cai, M.; Zhang, C.; Sawant, A.; Hinton, M.; Sathe, M.; Grein, J.; Blumenschein, W.; Pinheiro, E.M.; Chackerian, A. Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression. J. Clin. Invest.,  2018, 128(2), 644-654.
 [http://dx.doi.org/10.1172/JCI94586] [PMID:  29337311]

[43]
Shirsath, N.P.; Manohar, S.M.; Joshi, K.S. P276-00, a cyclin-dependent kinase inhibitor, modulates cell cycle and induces apoptosis in vitro and in vivo in mantle cell lymphoma cell lines. Mol. Cancer,  2012, 11(1), 77.
 [http://dx.doi.org/10.1186/1476-4598-11-77] [PMID:  23075291]

[44]
Cassaday, R.D.; Goy, A.; Advani, S.; Chawla, P.; Nachankar, R.; Gandhi, M.; Gopal, A.K. 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. Clin. Lymphoma Myeloma Leuk.,  2015, 15(7), 392-397.
 [http://dx.doi.org/10.1016/j.clml.2015.02.021] [PMID:  25816934]

[45]
Mishra, P.B.; Lobo, A.S.; Joshi, K.S.; Rathos, M.J.; Kumar, G.A.; Padigaru, M. Molecular mechanisms of anti-tumor properties of P276-00 in head and neck squamous cell carcinoma. J. Transl. Med.,  2013, 11(1), 42.
 [http://dx.doi.org/10.1186/1479-5876-11-42] [PMID:  23414419]

[46]
Su, Y.T.; Chen, R.; Wang, H.; Song, H.; Zhang, Q.; Chen, L.Y.; Lappin, H.; Vasconcelos, G.; Lita, A.; Maric, D.; Li, A.; Celiku, O.; Zhang, W.; Meetze, K.; Estok, T.; Larion, M.; Abu-Asab, M.; Zhuang, Z.; Yang, C.; Gilbert, M.R.; Wu, J. Novel targeting of transcription and metabolism in glioblastoma. Clin. Cancer Res.,  2018, 24(5), 1124-1137.
 [http://dx.doi.org/10.1158/1078-0432.CCR-17-2032] [PMID:  29254993]

[47]
Goh, K.C.; Novotny-Diermayr, V.; Hart, S.; Ong, L.C.; Loh, Y.K.; Cheong, A.; Tan, Y.C.; Hu, C.; Jayaraman, R.; William, A.D.; Sun, E.T.; Dymock, B.W.; Ong, K.H.; Ethirajulu, K.; Burrows, F.; Wood, J.M. TG02, a novel oral multi-kinase inhibitor of CDKs, JAK2 and FLT3 with potent anti-leukemic properties. Leukemia,  2012, 26(2), 236-243.
 [http://dx.doi.org/10.1038/leu.2011.218] [PMID:  21860433]

[48]
Ponder, K.G.; Matulis, S.M.; Hitosugi, S.; Gupta, V.A.; Sharp, C.; Burrows, F.; Nooka, A.K.; Kaufman, J.L.; Lonial, S.; Boise, L.H. Dual inhibition of Mcl-1 by the combination of carfilzomib and TG02 in multiple myeloma. Cancer Biol. Ther.,  2016, 17(7), 769-777.
 [http://dx.doi.org/10.1080/15384047.2016.1192086] [PMID:  27246906]

[49]
Dolman, M.E.M.; Poon, E.; Ebus, M.E.; den Hartog, I.J.M.; van Noesel, C.J.M.; Jamin, Y.; Hallsworth, A.; Robinson, S.P.; Petrie, K.; Sparidans, R.W.; Kok, R.J.; Versteeg, R.; Caron, H.N.; Chesler, L.; Molenaar, J.J. Cyclin-dependent kinase inhibitor AT7519 as a potential drug for MYCN-dependent neuroblastoma. Clin. Cancer Res.,  2015, 21(22), 5100-5109.
 [http://dx.doi.org/10.1158/1078-0432.CCR-15-0313] [PMID:  26202950]

[50]
Dorward, D.A.; Felton, J.M.; Robb, C.T.; Craven, T.; Kipari, T.; Walsh, T.S.; Haslett, C.; Kefala, K.; Rossi, A.G.; Lucas, C.D. The cyclin-dependent kinase inhibitor AT7519 accelerates neutrophil apoptosis in sepsis-related acute respiratory distress syndrome. Thorax,  2017, 72(2), 182-185.
 [http://dx.doi.org/10.1136/thoraxjnl-2016-209229] [PMID:  27965411]

[51]
Chen, E.X.; Hotte, S.; Hirte, H.; Siu, L.L.; Lyons, J.; Squires, M.; Lovell, S.; Turner, S.; McIntosh, L.; Seymour, L. A Phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177. Br. J. Cancer,  2014, 111(12), 2262-2267.
 [http://dx.doi.org/10.1038/bjc.2014.565] [PMID:  25393368]

[52]
Syn, N.L.; Lim, P.L.; Kong, L.R.; Wang, L.; Wong, A.L.A.; Lim, C.M.; Loh, T.K.S.; Siemeister, G.; Goh, B.C.; Hsieh, W.S. Pan-CDK inhibition augments cisplatin lethality in nasopharyngeal carcinoma cell lines and Xenograft models. Signal Transduct. Target. Ther.,  2018, 3(1), 9.
 [http://dx.doi.org/10.1038/s41392-018-0010-0] [PMID:  29666673]

[53]
Lin, S.F.; Lin, J.D.; Hsueh, C.; Chou, T.C.; Wong, R.J. Activity of roniciclib in medullary thyroid cancer. Oncotarget,  2018, 9(46), 28030-28041.
 [http://dx.doi.org/10.18632/oncotarget.25555] [PMID:  29963260]

[54]
Bahleda, R.; Grilley-Olson, J.E.; Govindan, R.; Barlesi, F.; Greillier, L.; Perol, M.; Ray-Coquard, I.; Strumberg, D.; Schultheis, B.; Dy, G.K.; Zalcman, G.; Weiss, G.J.; Walter, A.O.; Kornacker, M.; Rajagopalan, P.; Henderson, D.; Nogai, H.; Ocker, M.; Soria, J.C. Phase I dose-escalation studies of roniciclib, a pan-cyclin-dependent kinase inhibitor, in advanced malignancies. Br. J. Cancer,  2017, 116(12), 1505-1512.
 [http://dx.doi.org/10.1038/bjc.2017.92] [PMID:  28463960]

[55]
Cho, B.C.; Dy, G.K.; Govindan, R.; Kim, D.W.; Pennell, N.A.; Zalcman, G.; Besse, B.; Kim, J.H.; Koca, G.; Rajagopalan, P.; Langer, S.; Ocker, M.; Nogai, H.; Barlesi, F. Phase Ib/II study of the pan-cyclin-dependent kinase inhibitor roniciclib in combination with chemotherapy in patients with extensive-disease small-cell lung cancer. Lung Cancer,  2018, 123, 14-21.
 [http://dx.doi.org/10.1016/j.lungcan.2018.04.022] [PMID:  30089585]

[56]
Cirstea, D.; Hideshima, T.; Santo, L.; Eda, H.; Mishima, Y.; Nemani, N.; Hu, Y.; Mimura, N.; Cottini, F.; Gorgun, G.; Ohguchi, H.; Suzuki, R.; Loferer, H.; Munshi, N.C.; Anderson, K.C.; Raje, N. 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), 2366-2375.
 [http://dx.doi.org/10.1038/leu.2013.194] [PMID:  23807770]

[57]
van der Biessen, D.A.J.; Burger, H.; de Bruijn, P.; Lamers, C.H.J.; Naus, N.; Loferer, H.; Wiemer, E.A.C.; Mathijssen, R.H.J.; de Jonge, M.J.A. Phase I study of RGB-286638, a novel, multitargeted cyclin-dependent kinase inhibitor in patients with solid tumors. Clin. Cancer Res.,  2014, 20(18), 4776-4783.
 [http://dx.doi.org/10.1158/1078-0432.CCR-14-0325] [PMID:  25024258]

[58]
Locatelli, G.; Bosotti, R.; Ciomei, M.; Brasca, M.G.; Calogero, R.; Mercurio, C.; Fiorentini, F.; Bertolotti, M.; Scacheri, E.; Scaburri, A.; Galvani, A.; Pesenti, E.; De Baere, T.; Soria, J.C.; Lazar, V.; Isacchi, A. Transcriptional analysis of an E2F gene signature as a biomarker of activity of the cyclin-dependent kinase inhibitor PHA-793887 in tumor and skin biopsies from a phase I clinical study. Mol. Cancer Ther.,  2010, 9(5), 1265-1273.
 [http://dx.doi.org/10.1158/1535-7163.MCT-09-1163] [PMID:  20423997]

[59]
Alzani, R.; Pedrini, O.; Albanese, C.; Ceruti, R.; Casolaro, A.; Patton, V.; Colotta, F.; Rambaldi, A.; Introna, M.; Pesenti, E.; Ciomei, M.; Golay, J. Therapeutic efficacy of the pan-cdk inhibitor PHA-793887 in vitro and in vivo in engraftment and high-burden leukemia models. Exp. Hematol.,  2010, 38(4), 259-269.e2.
 [http://dx.doi.org/10.1016/j.exphem.2010.02.004] [PMID:  20167248]

[60]
Massard, C.; Soria, J.C.; Anthoney, D.A.; Proctor, A.; Scaburri, A.; Pacciarini, M.A.; Laffranchi, B.; Pellizzoni, C.; Kroemer, G.; Armand, J.P.; Balheda, R.; Twelves, C.J. A first in man, phase I dose-escalation study of PHA-793887, an inhibitor of multiple cyclin-dependent kinases (CDK2, 1 and 4) reveals unexpected hepatotoxicity in patients with solid tumors. Cell Cycle,  2011, 10(6), 963-970.
 [http://dx.doi.org/10.4161/cc.10.6.15075] [PMID:  21368575]

[61]
Gelbert, L.M.; Cai, S.; Lin, X.; Sanchez-Martinez, C.; del Prado, M.; Lallena, M.J.; Torres, R.; Ajamie, R.T.; Wishart, G.N.; Flack, R.S.; Neubauer, B.L.; Young, J.; Chan, E.M.; Iversen, P.; Cronier, D.; Kreklau, E.; de Dios, A. Preclinical characterization of the CDK4/6 inhibitor LY2835219: In-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest. New Drugs,  2014, 32(5), 825-837.
 [http://dx.doi.org/10.1007/s10637-014-0120-7] [PMID:  24919854]

[62]
Tripathy, D.; Bardia, A.; Sellers, W.R. Ribociclib (LEE011): Mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors. Clin. Cancer Res.,  2017, 23(13), 3251-3262.
 [http://dx.doi.org/10.1158/1078-0432.CCR-16-3157] [PMID:  28351928]

[63]
Klein, M.E.; Kovatcheva, M.; Davis, L.E.; Tap, W.D.; Koff, A. CDK4/6 inhibitors: The mechanism of action may not be as simple as once thought. Cancer Cell,  2018, 34(1), 9-20.
 [http://dx.doi.org/10.1016/j.ccell.2018.03.023] [PMID:  29731395]

[64]
Heathcote, D.A.; Patel, H.; Kroll, S.H.B.; Hazel, P.; Periyasamy, M.; Alikian, M.; Kanneganti, S.K.; Jogalekar, A.S.; Scheiper, B.; Barbazanges, M.; Blum, A.; Brackow, J.; Siwicka, A.; Pace, R.D.M.; Fuchter, M.J.; Snyder, J.P.; Liotta, D.C.; Freemont, P.S.; Aboagye, E.O.; Coombes, R.C.; Barrett, A.G.M.; Ali, S. 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. Med. Chem.,  2010, 53(24), 8508-8522.
 [http://dx.doi.org/10.1021/jm100732t] [PMID:  21080703]

[65]
Hazel, P.; Kroll, S.H.B.; Bondke, A.; Barbazanges, M.; Patel, H.; Fuchter, M.J.; Coombes, R.C.; Ali, S.; Barrett, A.G.M.; Freemont, P.S. Inhibitor selectivity for cyclin‐dependent kinase 7: A structural, thermodynamic, and modelling study. ChemMedChem,  2017, 12(5), 372-380.
 [http://dx.doi.org/10.1002/cmdc.201600535] [PMID:  28125165]

[66]
Patel, H.; Periyasamy, M.; Sava, G.P.; Bondke, A.; Slafer, B.W.; Kroll, S.H.B.; Barbazanges, M.; Starkey, R.; Ottaviani, S.; Harrod, A.; Aboagye, E.O.; Buluwela, L.; Fuchter, M.J.; Barrett, A.G.M.; Coombes, R.C.; Ali, S. ICEC0942, an orally bioavailable selective inhibitor of CDK7 for cancer treatment. Mol. Cancer Ther.,  2018, 17(6), 1156-1166.
 [http://dx.doi.org/10.1158/1535-7163.MCT-16-0847] [PMID:  29545334]

[67]
Chipumuro, E.; Marco, E.; Christensen, C.L.; Kwiatkowski, N.; Zhang, T.; Hatheway, C.M.; Abraham, B.J.; Sharma, B.; Yeung, C.; Altabef, A.; Perez-Atayde, A.; Wong, K.K.; Yuan, G.C.; Gray, N.S.; Young, R.A.; George, R.E. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell,  2014, 159(5), 1126-1139.
 [http://dx.doi.org/10.1016/j.cell.2014.10.024] [PMID:  25416950]

[68]
Christensen, C.L.; Kwiatkowski, N.; Abraham, B.J.; Carretero, J.; Al-Shahrour, F.; Zhang, T.; Chipumuro, E.; Herter-Sprie, G.S.; Akbay, E.A.; Altabef, A.; Zhang, J.; Shimamura, T.; Capelletti, M.; Reibel, J.B.; Cavanaugh, J.D.; Gao, P.; Liu, Y.; Michaelsen, S.R.; Poulsen, H.S.; Aref, A.R.; Barbie, D.A.; Bradner, J.E.; George, R.E.; Gray, N.S.; Young, R.A.; Wong, K-K. Erratum to Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell,  2015, 27(1), 149.
 [http://dx.doi.org/10.1016/j.ccell.2014.12.007]

[69]
Kwiatkowski, N.; Zhang, T.; Rahl, P.B.; Abraham, B.J.; Reddy, J.; Ficarro, S.B.; Dastur, A.; Amzallag, A.; Ramaswamy, S.; Tesar, B.; Jenkins, C.E.; Hannett, N.M.; McMillin, D.; Sanda, T.; Sim, T.; Kim, N.D.; Look, T.; Mitsiades, C.S.; Weng, A.P.; Brown, J.R.; Benes, C.H.; Marto, J.A.; Young, R.A.; Gray, N.S. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature,  2014, 511(7511), 616-620.
 [http://dx.doi.org/10.1038/nature13393] [PMID:  25043025]

[70]
Nagaraja, S.; Vitanza, N.A.; Woo, P.J.; Taylor, K.R.; Liu, F.; Zhang, L.; Li, M.; Meng, W.; Ponnuswami, A.; Sun, W.; Ma, J.; Hulleman, E.; Swigut, T.; Wysocka, J.; Tang, Y.; Monje, M. Transcriptional dependencies in diffuse intrinsic pontine glioma. Cancer Cell,  2017, 31(5), 635-652.e6.
 [http://dx.doi.org/10.1016/j.ccell.2017.03.011] [PMID:  28434841]

[71]
Wang, Y.; Zhang, T.; Kwiatkowski, N.; Abraham, B.J.; Lee, T.I.; Xie, S.; Yuzugullu, H.; Von, T.; Li, H.; Lin, Z.; Stover, D.G.; Lim, E.; Wang, Z.C.; Iglehart, J.D.; Young, R.A.; Gray, N.S.; Zhao, J.J. CDK7-dependent transcriptional addiction in triple-negative breast cancer. Cell,  2015, 163(1), 174-186.
 [http://dx.doi.org/10.1016/j.cell.2015.08.063] [PMID:  26406377]

[72]
Zhang, Y.; Zhou, L.; Bandyopadhyay, D.; Sharma, K.; Allen, A.J.; Kmieciak, M.; Grant, S. The covalent CDK7 inhibitor THZ1 potently induces apoptosis in multiple myeloma cells in vitro and in vivo. Clin. Cancer Res.,  2019, 25(20), 6195-6205.
 [http://dx.doi.org/10.1158/1078-0432.CCR-18-3788] [PMID:  31358538]

[73]
Olson, C.M.; Liang, Y.; Leggett, A.; Park, W.D.; Li, L.; Mills, C.E.; Elsarrag, S.Z.; Ficarro, S.B.; Zhang, T.; Düster, R.; Geyer, M.; Sim, T.; Marto, J.A.; Sorger, P.K.; Westover, K.D.; Lin, C.Y.; Kwiatkowski, N.; Gray, N.S. Development of a selective CDK7 covalent inhibitor reveals predominant cell-cycle phenotype. Cell Chem. Biol.,  2019, 26(6), 792-803.e10.
 [http://dx.doi.org/10.1016/j.chembiol.2019.02.012] [PMID:  30905681]

[74]
Hu, S.; Marineau, J.J.; Rajagopal, N.; Hamman, K.B.; Choi, Y.J.; Schmidt, D.R.; Ke, N.; Johannessen, L.; Bradley, M.J.; Orlando, D.A.; Alnemy, S.R.; Ren, Y.; Ciblat, S.; Winter, D.K.; Kabro, A.; Sprott, K.T.; Hodgson, J.G.; Fritz, C.C.; Carulli, J.P.; di Tomaso, E.; Olson, E.R. Discovery and characterization of SY-1365, a selective, covalent inhibitor of CDK7. Cancer Res.,  2019, 79(13), 3479-3491.
 [http://dx.doi.org/10.1158/0008-5472.CAN-19-0119] [PMID:  31064851]

[75]
Hu, S.; Marineau, J.; Hamman, K.; Bradley, M.; Savinainen, A.; Alnemy, S.; Rajagopal, N.; Orlando, D.; Chuaqui, C.; Olson, E. Abstract 4421: SY-5609, an orally available selective CDK7 inhibitor demonstrates broad anti-tumor activity in vivo. Cancer Res.,  2019, 79(Suppl. 13), 4421-4421.
 [http://dx.doi.org/10.1158/1538-7445.AM2019-4421]

[76]
Bacon, C.W.; D’Orso, I. CDK9: A signaling hub for transcriptional control. Transcription,  2019, 10(2), 57-75.
 [http://dx.doi.org/10.1080/21541264.2018.1523668] [PMID:  30227759]

[77]
Franco, L.C.; Morales, F.; Boffo, S.; Giordano, A. CDK9: A key player in cancer and other diseases. J. Cell. Biochem.,  2018, 119(2), 1273-1284.
 [http://dx.doi.org/10.1002/jcb.26293] [PMID:  28722178]

[78]
Cidado, J.; Boiko, S.; Proia, T.; Ferguson, D.; Criscione, S.W.; San Martin, M.; Pop-Damkov, P.; Su, N.; Roamio Franklin, V.N.; Sekhar Reddy Chilamakuri, C.; D’Santos, C.S.; Shao, W.; Saeh, J.C.; Koch, R.; Weinstock, D.M.; Zinda, M.; Fawell, S.E.; Drew, L. AZD4573 is a highly selective CDK9 inhibitor that suppresses MCL-1 and induces apoptosis in hematologic cancer cells. Clin. Cancer Res.,  2020, 26(4), 922-934.
 [http://dx.doi.org/10.1158/1078-0432.CCR-19-1853] [PMID:  31699827]

[79]
Wu, T.; Qin, Z.; Tian, Y.; Wang, J.; Xu, C.; Li, Z.; Bian, J. Recent developments in the biology and medicinal chemistry of CDK9 inhibitors: An update. J. Med. Chem.,  2020, 63(22), 13228-13257.
 [http://dx.doi.org/10.1021/acs.jmedchem.0c00744] [PMID:  32866383]

[80]
Anda, S.; Rothe, C.; Boye, E.; Grallert, B. Consequences of abnormal CDK activity in S phase. Cell Cycle,  2016, 15(7), 963-973.
 [http://dx.doi.org/10.1080/15384101.2016.1152423] [PMID:  26918805]

[81]
Galbraith, M.D.; Bender, H.; Espinosa, J.M. Therapeutic targeting of transcriptional cyclin-dependent kinases. Transcription,  2019, 10(2), 118-136.
 [http://dx.doi.org/10.1080/21541264.2018.1539615] [PMID:  30409083]

[82]
Choi, H.J.; Jin, S.; Cho, H.; Won, H.Y.; An, H.W.; Jeong, G.Y.; Park, Y.U.; Kim, H.Y.; Park, M.K.; Son, T.; Min, K.W.; Jang, K.S.; Oh, Y.H.; Lee, J.Y.; Kong, G. CDK 12 drives breast tumor initiation and trastuzumab resistance viaWNT and IRS 1‐ErbB‐ PI 3K signaling. EMBO Rep.,  2019, 20(10)e48058
 [http://dx.doi.org/10.15252/embr.201948058] [PMID:  31468695]

[83]
Peng, F.; Yang, C.; Kong, Y.; Huang, X.; Chen, Y.; Zhou, Y.; Xie, X.; Liu, P. CDK12 promotes breast cancer progression and maintains stemness by activating c-myc/β-catenin signaling. Curr. Cancer Drug Targets,  2020, 20(2), 156-165.
 [http://dx.doi.org/10.2174/1568009619666191118113220] [PMID:  31744448]

[84]
Hopkins, J.L.; Zou, L. Induction of BRCAness in triple-negative breast cancer by a CDK12/13 inhibitor improves chemotherapy. Cancer Cell,  2019, 36(5), 461-463.
 [http://dx.doi.org/10.1016/j.ccell.2019.10.012] [PMID:  31715127]

[85]
Quereda, V.; Bayle, S.; Vena, F.; Frydman, S.M.; Monastyrskyi, A.; Roush, W.R.; Duckett, D.R. Therapeutic targeting of CDK12/CDK13 in triple-negative breast cancer. Cancer Cell,  2019, 36(5), 545-558.e7.
 [http://dx.doi.org/10.1016/j.ccell.2019.09.004] [PMID:  31668947]

[86]
Zhang, T.; Kwiatkowski, N.; Olson, C.M.; Dixon-Clarke, S.E.; Abraham, B.J.; Greifenberg, A.K.; Ficarro, S.B.; Elkins, J.M.; Liang, Y.; Hannett, N.M.; Manz, T.; Hao, M.; Bartkowiak, B.; Greenleaf, A.L.; Marto, J.A.; Geyer, M.; Bullock, A.N.; Young, R.A.; Gray, N.S. Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat. Chem. Biol.,  2016, 12(10), 876-884.
 [http://dx.doi.org/10.1038/nchembio.2166] [PMID:  27571479]

[87]
Goel, S.; DeCristo, M.J.; Watt, A.C. BrinJones, H.; Sceneay, J.; Li, B.B.; Khan, N.; Ubellacker, J.M.; Xie, S.; Metzger-Filho, O.; Hoog, J.; Ellis, M.J.; Ma, C.X.; Ramm, S.; Krop, I.E.; Winer, E.P.; Roberts, T.M.; Kim, H.J.; McAllister, S.S.; Zhao, J.J. CDK4/6 inhibition triggers anti-tumour immunity. Nature,  2017, 548(7668), 471-475.
 [http://dx.doi.org/10.1038/nature23465] [PMID:  28813415]

[88]
Schaer, D.A.; Beckmann, R.P.; Dempsey, J.A.; Huber, L.; Forest, A.; Amaladas, N.; Li, Y.; Wang, Y.C.; Rasmussen, E.R.; Chin, D.; Capen, A.; Carpenito, C.; Staschke, K.A.; Chung, L.A.; Litchfield, L.M.; Merzoug, F.F.; Gong, X.; Iversen, P.W.; Buchanan, S.; de Dios, A.; Novosiadly, R.D.; Kalos, M. The CDK4/6 inhibitor abemaciclib induces a T cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade. Cell Rep.,  2018, 22(11), 2978-2994.
 [http://dx.doi.org/10.1016/j.celrep.2018.02.053] [PMID:  29539425]

[89]
Zhang, J.; Bu, X.; Wang, H.; Zhu, Y.; Geng, Y.; Nihira, N.T.; Tan, Y.; Ci, Y.; Wu, F.; Dai, X.; Guo, J.; Huang, Y.H.; Fan, C.; Ren, S.; Sun, Y.; Freeman, G.J.; Sicinski, P.; Wei, W. Cyclin D–CDK4 kinase destabilizes PD-L1 via cullin 3–SPOP to control cancer immune surveillance. Nature,  2018, 553(7686), 91-95.
 [http://dx.doi.org/10.1038/nature25015] [PMID:  29160310]

[90]
Kruse, U.; Pallasch, C.P.; Bantscheff, M.; Eberhard, D.; Frenzel, L.; Ghidelli, S.; Maier, S.K.; Werner, T.; Wendtner, C.M.; Drewes, G. Chemoproteomics-based kinome profiling and target deconvolution of clinical multi-kinase inhibitors in primary chronic lymphocytic leukemia cells. Leukemia,  2011, 25(1), 89-100.
 [http://dx.doi.org/10.1038/leu.2010.233] [PMID:  20944678]

[91]
Gao, N.; Dai, Y.; Rahmani, M.; Dent, P.; Grant, S. Contribution of disruption of the nuclear factor-kappaB pathway to induction of apoptosis in human leukemia cells by histone deacetylase inhibitors and flavopiridol. Mol. Pharmacol.,  2004, 66(4), 956-963.
 [http://dx.doi.org/10.1124/mol.104.002014] [PMID:  15235103]

[92]
Dai, Y.; Rahmani, M.; Grant, S. Proteasome inhibitors potentiate leukemic cell apoptosis induced by the cyclin-dependent kinase inhibitor flavopiridol through a SAPK/JNK- and NF-κB-dependent process. Oncogene,  2003, 22(46), 7108-7122.
 [http://dx.doi.org/10.1038/sj.onc.1206863] [PMID:  14562039]

[93]
Lin, T.S.; Blum, K.A.; Fischer, D.B.; Mitchell, S.M.; Ruppert, A.S.; Porcu, P.; Kraut, E.H.; Baiocchi, R.A.; Moran, M.E.; Johnson, A.J.; Schaaf, L.J.; Grever, M.R.; Byrd, J.C. Flavopiridol, fludarabine, and rituximab in mantle cell lymphoma and indolent B-cell lymphoproliferative disorders. J. Clin. Oncol.,  2010, 28(3), 418-423.
 [http://dx.doi.org/10.1200/JCO.2009.24.1570] [PMID:  20008633]

[94]
Wu, Y.M.; Cieślik, M.; Lonigro, R.J.; Vats, P.; Reimers, M.A.; Cao, X.; Ning, Y.; Wang, L.; Kunju, L.P.; de Sarkar, N.; Heath, E.I.; Chou, J.; Feng, F.Y.; Nelson, P.S.; de Bono, J.S.; Zou, W.; Montgomery, B.; Alva, A.; Robinson, D.R.; Chinnaiyan, A.M. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer. Cell,  2018, 173(7), 1770-1782.e14.
 [http://dx.doi.org/10.1016/j.cell.2018.04.034] [PMID:  29906450]

[95]
Li, Y.; Zhang, H.; Li, Q.; Zou, P.; Huang, X.; Wu, C.; Tan, L. CDK12/13 inhibition induces immunogenic cell death and enhances anti-PD-1 anticancer activity in breast cancer. Cancer Lett.,  2020, 495, 12-21.
 [http://dx.doi.org/10.1016/j.canlet.2020.09.011] [PMID:  32941949]

[96]
Siemeister, G.; Luecking, U.; Wagner, C.; Detjen, K.; Mc Coy, C.; Bosslet, K. Molecular and pharmacodynamic characteristics of the novel multi-target tumor growth inhibitor ZK 304709. Biomed. Pharmacother.,  2006, 60(6), 269-272.
 [http://dx.doi.org/10.1016/j.biopha.2006.06.003] [PMID:  16887322]

[97]
Cho, S.J.; Lee, S.S.; Kim, Y.J.; Park, B.D.; Choi, J.S.; Liu, L.; Ham, Y.M.; Moon Kim, B.; Lee, S.K. Xylocydine, a novel Cdk inhibitor, is an effective inducer of apoptosis in hepatocellular carcinoma cells in vitro and in vivo. Cancer Lett.,  2010, 287(2), 196-206.
 [http://dx.doi.org/10.1016/j.canlet.2009.06.011] [PMID:  19616371]

[98]
Ham, Y.M.; Choi, K.J.; Song, S.Y.; Jin, Y.H.; Chun, M.W.; Lee, S.K. Xylocydine, a novel inhibitor of cyclin-dependent kinases, prevents the tumor necrosis factor-related apoptosis-inducing ligand-induced apoptotic cell death of SK-HEP-1 cells. J. Pharmacol. Exp. Ther.,  2004, 308(3), 814-819.
 [http://dx.doi.org/10.1124/jpet.103.059568] [PMID:  14617691]

[99]
Wu, Y.; Chen, C.; Sun, X.; Shi, X.; Jin, B.; Ding, K.; Yeung, S.C.J.; Pan, J. Cyclin-dependent kinase 7/9 inhibitor SNS-032 abrogates FIP1-like-1 platelet-derived growth factor receptor α and bcr-abl oncogene addiction in malignant hematologic cells. Clin. Cancer Res.,  2012, 18(7), 1966-1978.
 [http://dx.doi.org/10.1158/1078-0432.CCR-11-1971] [PMID:  22447844]

[100]
Kamath, A.V.; Chong, S.; Chang, M.; Marathe, P.H. P-glycoprotein plays a role in the oral absorption of BMS-387032, a potent cyclin-dependent kinase 2 inhibitor, in rats. Cancer Chemother. Pharmacol.,  2005, 55(2), 110-116.
 [http://dx.doi.org/10.1007/s00280-004-0873-3] [PMID:  15338193]

[101]
Caligiuri, M.; Becker, F.; Murthi, K.; Kaplan, F.; Dedier, S.; Kaufmann, C.; Machl, A.; Zybarth, G.; Richard, J.; Bockovich, N.; Kluge, A.; Kley, N. A proteome-wide CDK/CRK-specific kinase inhibitor promotes tumor cell death in the absence of cell cycle progression. Chem. Biol.,  2005, 12(10), 1103-1115.
 [http://dx.doi.org/10.1016/j.chembiol.2005.08.008] [PMID:  16242653]

[102]
Gray, N.S.; Wodicka, L.; Thunnissen, A.M.W.H.; Norman, T.C.; Kwon, S.; Espinoza, F.H.; Morgan, D.O.; Barnes, G.; LeClerc, S.; Meijer, L.; Kim, S.H.; Lockhart, D.J.; Schultz, P.G. Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. Science,  1998, 281(5376), 533-538.
 [http://dx.doi.org/10.1126/science.281.5376.533] [PMID:  9677190]

[103]
Villerbu, N.; Gaben, A.M.; Redeuilh, G.; Mester, J. Cellular effects of purvalanol A: A specific inhibitor of cyclin-dependent kinase activities. Int. J. Cancer,  2002, 97(6), 761-769.
 [http://dx.doi.org/10.1002/ijc.10125] [PMID:  11857351]

[104]
Dhariwala, F.A.; Rajadhyaksha, M.S. An unusual member of the Cdk family: Cdk5. Cell. Mol. Neurobiol.,  2008, 28(3), 351-369.
 [http://dx.doi.org/10.1007/s10571-007-9242-1] [PMID:  18183483]
Rights & Permissions Print Cite
Article Metrics
95
4
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/1568009623666230320144713	Print ISSN 1568-0096
Publisher Name Bentham Science Publisher	Online ISSN 1873-5576
当代肿瘤药物靶点

CDK酶抑制剂在癌症治疗中的应用综述

摘要

图形摘要

Innovative Cancer Drug Targets: A New Horizon in Oncology

Role of Immune and Genotoxic Response Biomarkers in Tumor Microenvironment in Cancer Diagnosis and Treatment

The Impact of Cancer Neuroscience on Novel Brain Cancer Treatment

Unraveling the Tumor Microenvironment and Potential Therapeutic Targets: Insights from Single-Cell Sequencing and Spatial Transcriptomics

当代肿瘤药物靶点

CDK酶抑制剂在癌症治疗中的应用综述

摘要

图形摘要

Call for Papers in Thematic Issues

Innovative Cancer Drug Targets: A New Horizon in Oncology

Role of Immune and Genotoxic Response Biomarkers in Tumor Microenvironment in Cancer Diagnosis and Treatment

The Impact of Cancer Neuroscience on Novel Brain Cancer Treatment

Unraveling the Tumor Microenvironment and Potential Therapeutic Targets: Insights from Single-Cell Sequencing and Spatial Transcriptomics

Related Journals

Related Books
