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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Review Article

Small Molecule CDK Inhibitors for the Therapeutic Management of Cancer

Author(s): Bharat Goel, Nancy Tripathi, Nivedita Bhardwaj and Shreyans K. Jain*

Volume 20 , Issue 17 , 2020

Page: [1535 - 1563] Pages: 29

DOI: 10.2174/1568026620666200516152756

Price: $65


Cyclin-dependent kinases (CDKs) are a group of multifunctional enzymes consisting of catalytic and regulatory subunits. The regulatory subunit, cyclin, remains dissociated under normal circumstances, and complexation of cyclin with the catalytic subunit of CDK leads to its activation for phosphorylation of protein substrates. The primary role of CDKs is in the regulation of the cell cycle. Retinoblastoma protein (Rb) is one of the widely investigated tumor suppressor protein substrates of CDK, which prevents cells from entering into cell-cycle under normal conditions. Phosphorylation of Rb by CDKs causes its inactivation and ultimately allows cells to enter a new cell cycle. Many cancers are associated with hyperactivation of CDKs as a result of mutation of the CDK genes or CDK inhibitor genes. Therefore, CDK modulators are of great interest to explore as novel therapeutic agents against cancer and led to the discovery of several CDK inhibitors to clinics. This review focuses on the current progress and development of anti-cancer CDK inhibitors from preclinical to clinical and synthetic to natural small molecules.

Keywords: Cyclin-dependent kinase, CDK inhibitors, Cell cycle, Clinical trial, Cancer, Natural products.

Graphical Abstract
Malumbres, M.; Barbacid, M. To cycle or not to cycle: a critical decision in cancer. Nat. Rev. Cancer, 2001, 1(3), 222-231.
[] [PMID: 11902577]
Harper, J.W.; Adams, P.D. Cyclin-dependent kinases. Chem. Rev., 2001, 101(8), 2511-2526.
[] [PMID: 11749386]
Malumbres, M. Cyclin-dependent kinases. Genome Biol., 2014, 15(6), 122.
[] [PMID: 25180339]
Pavletich, N.P. Mechanisms of cyclin-dependent kinase regulation: structures of Cdks, their cyclin activators, and Cip and INK4 inhibitors. J. Mol. Biol., 1999, 287(5), 821-828.
[] [PMID: 10222191]
Malumbres, M.; Barbacid, M. Mammalian cyclin-dependent kinases. Trends Biochem. Sci., 2005, 30(11), 630-641.
[] [PMID: 16236519]
Lim, S.; Kaldis, P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation. Development, 2013, 140(15), 3079-3093.
[] [PMID: 23861057]
Kalra, S.; Joshi, G.; Munshi, A.; Kumar, R. Structural insights of cyclin dependent kinases: Implications in design of selective inhibitors. Eur. J. Med. Chem., 2017, 142, 424-458.
[] [PMID: 28911822]
Cobrinik, D. Pocket proteins and cell cycle control. Oncogene, 2005, 24(17), 2796-2809.
[] [PMID: 15838516]
Ren, S.; Rollins, B.J. Cyclin C/cdk3 promotes Rb-dependent G0 exit. Cell, 2004, 117(2), 239-251.
[] [PMID: 15084261]
Egloff, S.; Dienstbier, M.; Murphy, S. Updating the RNA polymerase CTD code: adding gene-specific layers. Trends Genet., 2012, 28(7), 333-341.
[] [PMID: 22622228]
Larochelle, S.; Amat, R.; Glover-Cutter, K.; Sansó, M.; Zhang, C.; Allen, J.J.; Shokat, K.M.; Bentley, D.L.; Fisher, R.P. Cyclin dependent kinase control of the initiation-to-elongation switch of RNA polymerase II. Nat. Struct. Mol. Biol., 2012, 19(11), 1108-1115.
[] [PMID: 23064645]
Tien, J.F.; Mazloomian, A.; Cheng, S.G.; Hughes, C.S.; Chow, C.C.T.; Canapi, L.T.; Oloumi, A.; Trigo-Gonzalez, G.; Bashashati, A.; Xu, J.; Chang, V.C.D.; Shah, S.P.; Aparicio, S.; Morin, G.B. CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion. Nucleic Acids Res., 2017, 45(11), 6698-6716.
[] [PMID: 28334900]
Lei, T.; Zhang, P.; Zhang, X.; Xiao, X.; Zhang, J.; Qiu, T.; Dai, Q.; Zhang, Y.; Min, L.; Li, Q.; Yin, R.; Ding, P.; Li, N.; Qu, Y.; Mu, D.; Qin, J.; Zhu, X.; Xiao, Z-X.; Li, Q. Cyclin K regulates prereplicative complex assembly to promote mammalian cell proliferation. Nat. Commun., 2018, 9(1), 1876.
[] [PMID: 29760377]
Blazek, D.; Kohoutek, J.; Bartholomeeusen, K.; Johansen, E.; Hulinkova, P.; Luo, Z.; Cimermancic, P.; Ule, J.; Peterlin, B.M. The Cyclin K/Cdk12 complex maintains genomic stability via regulation of expression of DNA damage response genes. Genes Dev., 2011, 25(20), 2158-2172.
[] [PMID: 22012619]
Greifenberg, A.K.; Hönig, D.; Pilarova, K.; Düster, R.; Bartholomeeusen, K.; Bösken, C.A.; Anand, K.; Blazek, D.; Geyer, M. Structural and functional analysis of the cdk13/cyclin k complex. Cell Rep., 2016, 14(2), 320-331.
[] [PMID: 26748711]
Bostwick, B.L.; McLean, S.; Posey, J.E.; Streff, H.E.; Gripp, K.W.; Blesson, A.; Powell-Hamilton, N.; Tusi, J.; Stevenson, D.A.; Farrelly, E.; Hudgins, L.; Yang, Y.; Xia, F.; Wang, X.; Liu, P.; Walkiewicz, M.; McGuire, M.; Grange, D.K.; Andrews, M.V.; Hummel, M.; Madan-Khetarpal, S.; Infante, E.; Coban-Akdemir, Z.; Miszalski-Jamka, K.; Jefferies, J.L.; Rosenfeld, J.A.; Emrick, L.; Nugent, K.M.; Lupski, J.R.; Belmont, J.W.; Lee, B.; Lalani, S.R. Members of the Undiagnosed Diseases Network. Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders. Genome Med., 2017, 9(1), 73.
[] [PMID: 28807008]
Carlsten, J.O.; Zhu, X.; Gustafsson, C.M. The multitalented Mediator complex. Trends Biochem. Sci., 2013, 38(11), 531-537.
[] [PMID: 24074826]
Besson, A.; Dowdy, S.F.; Roberts, J.M. CDK inhibitors: cell cycle regulators and beyond. Dev. Cell, 2008, 14(2), 159-169.
[] [PMID: 18267085]
Jeffrey, P.D.; Tong, L.; Pavletich, N.P. Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors. Genes Dev., 2000, 14(24), 3115-3125.
[] [PMID: 11124804]
Diaz-Moralli, S.; Tarrado-Castellarnau, M.; Miranda, A.; Cascante, M. Targeting cell cycle regulation in cancer therapy. Pharmacol. Ther., 2013, 138(2), 255-271.
[] [PMID: 23356980]
Michalides, R.; van Veelen, N.; Hart, A.; Loftus, B.; Wientjens, E.; Balm, A. Overexpression of cyclin D1 correlates with recurrence in a group of forty-seven operable squamous cell carcinomas of the head and neck. Cancer Res., 1995, 55(5), 975-978.
[PMID: 7867006]
Malumbres, M.; Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer, 2009, 9(3), 153-166.
[] [PMID: 19238148]
Musacchio, A.; Salmon, E.D. The spindle-assembly checkpoint in space and time. Nat. Rev. Mol. Cell Biol., 2007, 8(5), 379-393.
[] [PMID: 17426725]
Cicenas, J.; Valius, M. The CDK inhibitors in cancer research and therapy. J. Cancer Res. Clin. Oncol., 2011, 137(10), 1409-1418.
[] [PMID: 21877198]
McDermott, M.S.J.; Sharko, A.C.; Munie, J.; Kassler, S.; Melendez, T.; Lim, C.U.; Broude, E.V. CDK7 inhibition is effective in all the subtypes of breast cancer: determinants of response and synergy with egfr inhibition. Cells, 2020, 9(3), E638.
[]] [PMID: 32155786]
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.
[] [PMID: 26406377]
Tadesse, S.; Caldon, E.C.; Tilley, W.; Wang, S. Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update. J. Med. Chem., 2019, 62(9), 4233-4251.
[] [PMID: 30543440]
Geng, Y.; Yu, Q.; Sicinska, E.; Das, M.; Schneider, J.E.; Bhattacharya, S.; Rideout, W.M.; Bronson, R.T.; Gardner, H.; Sicinski, P.; Cyclin, E. Cyclin E ablation in the mouse. Cell, 2003, 114(4), 431-443.
[] [PMID: 12941272]
Wang, J.; Yang, T.; Xu, G.; Liu, H.; Ren, C.; Xie, W.; Wang, M. Cyclin-dependent kinase 2 promotes tumor proliferation and induces radio resistance in glioblastoma. Transl. Oncol., 2016, 9(6), 548-556.
[] [PMID: 27863310]
Faber, A.C.; Chiles, T.C. Inhibition of cyclin-dependent kinase-2 induces apoptosis in human diffuse large B-cell lymphomas. Cell Cycle, 2007, 6(23), 2982-2989.
[] [PMID: 18156799]
Trowbridge, J.M.; Rogatsky, I.; Garabedian, M.J. Regulation of estrogen receptor transcriptional enhancement by the cyclin A/Cdk2 complex. Proc. Natl. Acad. Sci. USA, 1997, 94(19), 10132-10137.
[] [PMID: 9294175]
Yin, X.; Yu, J.; Zhou, Y.; Wang, C.; Jiao, Z.; Qian, Z.; Sun, H.; Chen, B. Identification of CDK2 as a novel target in treatment of prostate cancer. Future Oncol., 2018, 14(8), 709-718.
[] [PMID: 29323532]
Li, J-Q.; Miki, H.; Ohmori, M.; Wu, F.; Funamoto, Y. Expression of cyclin E and cyclin-dependent kinase 2 correlates with metastasis and prognosis in colorectal carcinoma. Hum. Pathol., 2001, 32(9), 945-953.
[] [PMID: 11567224]
Ahn, M.J.; Kim, B.H.; Jang, S.J.; Hong, E.K.; Lee, W.M.; Baik, H.K.; Park, H.K.; Lee, C.B.; Ki, M. Expression of cyclin D1 and cyclin E in human gastric carcinoma and its clinicopathologic significance. J. Korean Med. Sci., 1998, 13(5), 513-518.
[] [PMID: 9811181]
Mohammadizadeh, F.; Hani, M.; Ranaee, M.; Bagheri, M. Role of cyclin D1 in breast carcinoma. J. Res. Med. Sci., 2013, 18(12), 1021-1025.
Michalides, R.; Hageman, P.; van Tinteren, H.; Houben, L.; Wientjens, E.; Klompmaker, R.; Peterse, J. A clinicopathological study on overexpression of cyclin D1 and of p53 in a series of 248 patients with operable breast cancer. Br. J. Cancer, 1996, 73(6), 728-734.
[] [PMID: 8611372]
Foster, J.S.; Wimalasena, J. Estrogen regulates activity of cyclin-dependent kinases and retinoblastoma protein phosphorylation in breast cancer cells. Mol. Endocrinol., 1996, 10(5), 488-498.
[PMID: 8732680]
Roy, P.G.; Thompson, A.M. Cyclin D1 and breast cancer. Breast, 2006, 15(6), 718-727.
[] [PMID: 16675218]
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.
[] [PMID: 25633797]
Burkhart, D.L.; Sage, J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat. Rev. Cancer, 2008, 8(9), 671-682.
[] [PMID: 18650841]
Bartkova, J.; Rezaei, N.; Liontos, M.; Karakaidos, P.; Kletsas, D.; Issaeva, N.; Vassiliou, L-V.F.; Kolettas, E.; Niforou, K.; Zoumpourlis, V.C.; Takaoka, M.; Nakagawa, H.; Tort, F.; Fugger, K.; Johansson, F.; Sehested, M.; Andersen, C.L.; Dyrskjot, L.; Ørntoft, T.; Lukas, J.; Kittas, C.; Helleday, T.; Halazonetis, T.D.; Bartek, J.; Gorgoulis, V.G. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature, 2006, 444(7119), 633-637.
[] [PMID: 17136093]
LaPak, K.M.; Burd, C.E. The molecular balancing act of p16(INK4a) in cancer and aging. Mol. Cancer Res., 2014, 12(2), 167-183.
[] [PMID: 24136988]
Witkiewicz, A.K.; Knudsen, K.E.; Dicker, A.P.; Knudsen, E.S. The meaning of p16(ink4a) expression in tumors: functional significance, clinical associations and future developments. Cell Cycle, 2011, 10(15), 2497-2503.
[] [PMID: 21775818]
Knudsen, K.E.; Diehl, J.A.; Haiman, C.A.; Knudsen, E.S. Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene, 2006, 25(11), 1620-1628.
[] [PMID: 16550162]
Wölfel, T.; Hauer, M.; Schneider, J.; Serrano, M.; Wölfel, C.; Klehmann-Hieb, E.; De Plaen, E.; Hankeln, T.; Meyer zum Büschenfelde, K.H.; Beach, D.A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T lymphocytes in a human melanoma. Science, 1995, 269(5228), 1281-1284.
[] [PMID: 7652577]
Sever-Chroneos, Z.; Angus, S.P.; Fribourg, A.F.; Wan, H.; Todorov, I.; Knudsen, K.E.; Knudsen, E.S. Retinoblastoma tumor suppressor protein signals through inhibition of cyclin-dependent kinase 2 activity to disrupt PCNA function in S phase. Mol. Cell. Biol., 2001, 21(12), 4032-4045.
[] [PMID: 11359910]
Markey, M.P.; Angus, S.P.; Strobeck, M.W.; Williams, S.L.; Gunawardena, R.W.; Aronow, B.J.; Knudsen, E.S. Unbiased analysis of RB-mediated transcriptional repression identifies novel targets and distinctions from E2F action. Cancer Res., 2002, 62(22), 6587-6597.
[PMID: 12438254]
Polyak, K.; Lee, M-H.; Erdjument-Bromage, H.; Koff, A.; Roberts, J.M.; Tempst, P.; Massagué, J. Cloning of p27Kip1, a cyclin dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell, 1994, 78(1), 59-66.
[] [PMID: 8033212]
Wu, C-L.; Kirley, S.D.; Xiao, H.; Chuang, Y.; Chung, D.C.; Zukerberg, L.R. Cables enhances cdk2 tyrosine 15 phosphorylation by Wee1, inhibits cell growth, and is lost in many human colon and squamous cancers. Cancer Res., 2001, 61(19), 7325-7332.
[PMID: 11585773]
Scaltriti, M.; Eichhorn, P.J.; Cortés, J.; Prudkin, L.; Aura, C.; Jiménez, J.; Chandarlapaty, S.; Serra, V.; Prat, A.; Ibrahim, Y.H.; Guzmán, M.; Gili, M.; Rodríguez, O.; Rodríguez, S.; Pérez, J.; Green, S.R.; Mai, S.; Rosen, N.; Hudis, C.; Baselga, J. Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients. Proc. Natl. Acad. Sci. USA, 2011, 108(9), 3761-3766.
[] [PMID: 21321214]
Lukas, J.; Herzinger, T.; Hansen, K.; Moroni, M.C.; Resnitzky, D.; Helin, K.; Reed, S.I.; Bartek, J. Cyclin E-induced S phase without activation of the pRb/E2F pathway. Genes Dev., 1997, 11(11), 1479-1492.
[] [PMID: 9192874]
Hammerman, P.S.; Lawrence, M.S.; Voet, D.; Jing, R.; Cibulskis, K.; Sivachenko, A.; Stojanov, P.; McKenna, A.; Lander, E.S.; Gabriel, S.; Getz, G.; Sougnez, C.; Imielinski, M.; Helman, E.; Hernandez, B.; Pho, N.H.; Meyerson, M.; Chu, A.; Chun, H-J.E.; Mungall, A.J.; Pleasance, E.; Gordon Robertson, A.; Sipahimalani, P.; Stoll, D.; Balasundaram, M.; Birol, I.; Butterfield, Y.S.N.; Chuah, E.; Coope, R.J.N.; Corbett, R.; Dhalla, N.; Guin, R.; He, A.; Hirst, C.; Hirst, M.; Holt, R.A.; Lee, D.; Li, H.I.; Mayo, M.; Moore, R.A.; Mungall, K.; Ming Nip, K.; Olshen, A.; Schein, J.E.; Slobodan, J.R.; Tam, A.; Thiessen, N.; Varhol, R.; Zeng, T.; Zhao, Y.; Jones, S.J.M.; Marra, M.A.; Saksena, G.; Cherniack, A.D.; Schumacher, S.E.; Tabak, B.; Carter, S.L.; Pho, N.H.; Nguyen, H.; Onofrio, R.C.; Crenshaw, A.; Ardlie, K.; Beroukhim, R.; Winckler, W.; Hammerman, P.S.; Getz, G.; Meyerson, M.; Protopopov, A.; Zhang, J.; Hadjipanayis, A.; Lee, S.; Xi, R.; Yang, L.; Ren, X.; Zhang, H.; Shukla, S.; Chen, P-C.; Haseley, P.; Lee, E.; Chin, L.; Park, P.J.; Kucherlapati, R.; Socci, N.D.; Liang, Y.; Schultz, N.; Borsu, L.; Lash, A.E.; Viale, A.; Sander, C.; Ladanyi, M.; Todd Auman, J.; Hoadley, K.A.; Wilkerson, M.D.; Shi, Y.; Liquori, C.; Meng, S.; Li, L.; Turman, Y.J.; Topal, M.D.; Tan, D.; Waring, S.; Buda, E.; Walsh, J.; Jones, C.D.; Mieczkowski, P.A.; Singh, D.; Wu, J.; Gulabani, A.; Dolina, P.; Bodenheimer, T.; Hoyle, A.P.; Simons, J.V.; Soloway, M.G.; Mose, L.E.; Jefferys, S.R.; Balu, S.; O’Connor, B.D.; Prins, J.F.; Liu, J.; Chiang, D.Y.; Neil Hayes, D.; Perou, C.M.; Cope, L.; Danilova, L.; Weisenberger, D.J.; Maglinte, D.T.; Pan, F.; Van Den Berg, D.J.; Triche Jr, T.; Herman, J.G.; Baylin, S.B.; Laird, P.W.; Getz, G.; Noble, M.; Voet, D.; Saksena, G.; Gehlenborg, N.; DiCara, D.; Zhang, J.; Zhang, H.; Wu, C-J.; Liu, Y. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature, 2012, 489(7417), 519-525.
[] [PMID: 22960745]
Weinstein, J.N.; Akbani, R.; Broom, B.M.; Wang, W.; Verhaak, R.G.W.; McConkey, D.; Lerner, S.; Morgan, M.; Creighton, C.J.; Smith, C.; Kwiatkowski, D.J.; Cherniack, A.D.; Kim, J.; Sekhar Pedamallu, C.; Noble, M.S.; Al-Ahmadie, H.A.; Reuter, V.E.; Rosenberg, J.E.; Bajorin, D.F.; Bochner, B.H.; Solit, D.B.; Koppie, T.; Robinson, B.; Gordenin, D.A.; Fargo, D.; Klimczak, L.J.; Roberts, S.A.; Au, J.; Laird, P.W.; Hinoue, T.; Schultz, N.; Ramirez, R.; Hansel, D.; Hoadley, K.A.; Kim, W.Y.; Damrauer, J.S.; Baylin, S.B.; Mungall, A.J.; Gordon Robertson, A.; Chu, A.; Kwiatkowski, D.J.; Sougnez, C.; Cibulskis, K.; Lichtenstein, L.; Sivachenko, A.; Stewart, C.; Lawrence, M.S.; Getz, G.; Lander, E.; Gabriel, S.B.; Creighton, C.J.; Donehower, L.; Cherniack, A.D.; Kim, J.; Carter, S.L.; Saksena, G.; Schumacher, S.E.; Sougnez, C.; Freeman, S.S.; Jung, J.; Sekhar Pedamallu, C.; Bhatt, A.S.; Pugh, T.; Getz, G.; Beroukhim, R.; Gabriel, S.B.; Meyerson, M.; Mungall, A.J.; Gordon Robertson, A.; Chu, A.; Ally, A.; Balasundaram, M.; Butterfield, Y.S.N.; Dhalla, N.; Hirst, C.; Holt, R.A.; Jones, S.J.M.; Lee, D.; Li, H.I.; Marra, M.A.; Mayo, M.; Moore, R.A.; Schein, J.E.; Sipahimalani, P.; Tam, A.; Thiessen, N.; Wong, T.; Wye, N.; Bowlby, R.; Chuah, E.; Guin, R.; Jones, S.J.M.; Marra, M.A.; Hinoue, T.; Shen, H.; Bootwalla, M.S.; Triche Jr, T.; Lai, P.H.; Van Den Berg, D.J.; Weisenberger, D.J.; Laird, P.W.; Hansel, D.; Hoadley, K.A.; Balu, S.; Bodenheimer, T.; Damrauer Alan, P. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature, 2014, 507(7492), 315-322.
[] [PMID: 24476821]
Leone, P.E.; Walker, B.A.; Jenner, M.W.; Chiecchio, L.; Dagrada, G.; Protheroe, R.K.M.; Johnson, D.C.; Dickens, N.J.; Brito, J.L.; Else, M.; Gonzalez, D.; Ross, F.M.; Chen-Kiang, S.; Davies, F.E.; Morgan, G.J. Deletions of CDKN2C in multiple myeloma: biological and clinical implications. Clin. Cancer Res., 2008, 14(19), 6033-6041.
[] [PMID: 18829482]
Bell, D.; Berchuck, A.; Birrer, M.; Chien, J.; Cramer, D.W.; Dao, F.; Dhir, R.; DiSaia, P.; Gabra, H.; Glenn, P.; Godwin, A.K.; Gross, J.; Hartmann, L.; Huang, M.; Huntsman, D.G.; Iacocca, M.; Imielinski, M.; Kalloger, S.; Karlan, B.Y.; Levine, D.A.; Mills, G.B.; Morrison, C.; Mutch, D.; Olvera, N.; Orsulic, S.; Park, K.; Petrelli, N.; Rabeno, B.; Rader, J.S.; Sikic, B.I.; Smith-McCune, K.; Sood, A.K.; Bowtell, D.; Penny, R.; Testa, J.R.; Chang, K.; Creighton, C.J.; Dinh, H.H.; Drummond, J.A.; Fowler, G.; Gunaratne, P.; Hawes, A.C.; Kovar, C.L.; Lewis, L.R.; Morgan, M.B.; Newsham, I.F.; Santibanez, J.; Reid, J.G.; Trevino, L.R.; Wu, Y.Q.; Wang, M.; Muzny, D.M.; Wheeler, D.A.; Gibbs, R.A.; Getz, G.; Lawrence, M.S.; Cibulskis, K.; Sivachenko, A.Y.; Sougnez, C.; Voet, D.; Wilkinson, J.; Bloom, T.; Ardlie, K.; Fennell, T.; Baldwin, J.; Nichol, R.; Fisher, S.; Gabriel, S.; Lander, E.S.; Ding, L.; Fulton, R.S.; Koboldt, D.C.; McLellan, M.D.; Wylie, T.; Walker, J.; O’Laughlin, M.; Dooling, D.J.; Fulton, L.; Abbott, R.; Dees, N.D.; Zhang, Q.; Kandoth, C.; Wendl, M.; Schierding, W.; Shen, D.; Harris, C.C.; Schmidt, H.; Kalicki, J.; Delehaunty, K.D.; Fronick, C.C.; Demeter, R.; Cook, L.; Wallis, J.W.; Lin, L.; Magrini, V.J.; Hodges, J.S.; Eldred, J.M.; Smith, S.M.; Pohl, C.S.; Vandin, F.; Upfal, E.; Raphael, B.J.; Weinstock, G.M.; Mardis, E.R.; Wilson, R.K.; Meyerson, M.; Winckler, W.; Getz, G.; Verhaak, R.G.W.; Carter, S.L.; Mermel, C.H.; Saksena, G.; Nguyen, H.; Onofrio, R.C.; Lawrence, M.S.; Hubbard, D.; Gupta, S.; Crenshaw, A.; Ramos, A.H.; Ardlie, K.; Chin, L.; Protopopov, A.; Zhang, J.; Kim, T.M.; Perna, I.; Xiao, Y.; Zhang, H.; Ren, G.; Sathiamoorthy, N.; Park, R.W.; Lee, E.; Park, P.J.; Kucherlapati, R.; Absher, D.M.; Waite, L.; Sherlock, G.; Brooks, J.D.; Li, J.Z.; Xu, J.; Myers, R.M.; Laird, P.W.; Cope, L.; Herman, J.G.; Shen, H.; Weisenberger, D.J.; Noushmehr, H.; Pan, F.; Triche, T., Jr; Berman, B.P.; Van Den Berg, D.J.; Buckley, J.; Baylin, S.B.; Spellman, P.T.; Purdom, E.; Neuvial, P.; Bengtsson, H.; Jakkula, L.R.; Durinck, S.; Han, J.; Dorton, S.; Marr, H.; Choi, Y.G.; Wang, V.; Wang, N.J.; Ngai, J.; Conboy, J.G.; Parvin, B.; Feiler, H.S.; Speed, T.P.; Gray, J.W.; Levine, D.A.; Socci, N.D.; Liang, Y.; Taylor, B.S.; Schultz, N.; Borsu, L.; Lash, A.E.; Brennan, C.; Viale, A.; Sander, C.; Ladanyi, M.; Hoadley, K.A.; Meng, S.; Du, Y.; Shi, Y.; Li, L.; Turman, Y.J.; Zang, D.; Helms, E.B.; Balu, S.; Zhou, X.; Wu, J.; Topal, M.D.; Hayes, D.N.; Perou, C.M.; Getz, G.; Voet, D.; Saksena, G.; Zhang, J.; Zhang, H.; Wu, C.J.; Shukla, S.; Cibulskis, K.; Lawrence, M.S.; Sivachenko, A.; Jing, R.; Park, R.W.; Liu, Y.; Park, P.J.; Noble, M.; Chin, L.; Carter, H.; Kim, D.; Samayoa, J.; Karchin, R.; Spellman, P.T.; Purdom, E.; Neuvial, P.; Bengtsson, H.; Durinck, S.; Han, J.; Korkola, J.E.; Heiser, L.M.; Cho, R.J.; Hu, Z.; Parvin, B.; Speed, T.P.; Gray, J.W.; Schultz, N.; Cerami, E.; Taylor, B.S.; Olshen, A.; Reva, B.; Antipin, Y.; Shen, R.; Mankoo, P.; Sheridan, R.; Ciriello, G.; Chang, W.K.; Bernanke, J.A.; Borsu, L.; Levin, D.A.; Ladanyi, M.; Sander, C.; Haussler, D.; Benz, C.C.; Stuart, J.M.; Benz, S.C.; Sanborn, J.Z.; Vaske, C.J.; Zhu, J.; Szeto, C.; Scott, G.K.; Yau, C.; Hoadley, K.A.; Du, Y.; Balu, S.; Hayes, D.N.; Perou, C.M.; Wilkerson, M.D.; Zhang, N.; Akbani, R.; Baggerly, K.A.; Yung, W.K.; Mills, G.B.; Weinstein, J.N.; Penny, R.; Shelton, T.; Grimm, D.; Hatfield, M.; Morris, S.; Yena, P.; Rhodes, P.; Sherman, M.; Paulauskis, J.; Millis, S.; Kahn, A.; Greene, J.M. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature, 2011, 474(7353), 609-615.
[] [PMID: 21720365]
Cazier, J.B.; Rao, S.R.; McLean, C.M.; Walker, A.K.; Wright, B.J.; Jaeger, E.E.M.; Kartsonaki, C.; Marsden, L.; Yau, C.; Camps, C.; Kaisaki, P.; Taylor, J.; Catto, J.W.; Tomlinson, I.P.; Kiltie, A.E.; Hamdy, F.C.; Buck, D.; Cazier, J-B.; Copley, R.; Cornall, R.; Donnelly, P.; Fiddy, S.; Green, A.; Gregory, L.; Grocock, R.; Hatton, E.; Holmes, C.; Hughes, L.; Humburg, P.; Humphray, S.; Kanapin, A.; Kingsbury, Z.; Knight, J.; Lamble, S.; Lise, S.; Lonie, L.; Lunter, G.; Martin, H.; Murray, L.; McCarthy, D.; McVean, G.; Pagnamenta, A.; Piazza, P.; Polanco, G.; Ratcliffe, P.; Rimmer, A.; Sahgal, N.; Taylor, J.; Tomlinson, I.; Trebes, A.; Wilkie, A.; Wright, B.; Yau, C.; Taylor, J.; Catto, J.W.; Tomlinson, I.P.M.; Kiltie, A.E.; Hamdy, F.C. Oxford-Illumina WGS500 Consortium. Whole-genome sequencing of bladder cancers reveals somatic CDKN1A mutations and clinicopathological associations with mutation burden. Nat. Commun., 2014, 5(1), 3756.
[] [PMID: 24777035]
Abbas, T.; Dutta, A. p21 in cancer: intricate networks and multiple activities. Nat. Rev. Cancer, 2009, 9(6), 400-414.
[] [PMID: 19440234]
Caffo, O.; Doglioni, C.; Veronese, S.; Bonzanini, M.; Marchetti, A.; Buttitta, F.; Fina, P.; Leek, R.; Morelli, L.; Palma, P.D.; Harris, A.L.; Barbareschi, M. Prognostic value of p21(WAF1) and p53 expression in breast carcinoma: an immunohistochemical study in 261 patients with long-term follow-up. Clin. Cancer Res., 1996, 2(9), 1591-1599.
[PMID: 9816338]
Dhavan, R.; Tsai, L-H. A decade of CDK5. Nat. Rev. Mol. Cell Biol., 2001, 2(10), 749-759.
[] [PMID: 11584302]
Su, S.C.; Tsai, L-H. Cyclin-dependent kinases in brain development and disease. Annu. Rev. Cell Dev. Biol., 2011, 27(1), 465-491.
[] [PMID: 21740229]
Zheng, Y-L.; Amin, N.D.; Hu, Y-F.; Rudrabhatla, P.; Shukla, V.; Kanungo, J.; Kesavapany, S.; Grant, P.; Albers, W.; Pant, H.C. A 24-residue peptide (p5), derived from p35, the Cdk5 neuronal activator, specifically inhibits Cdk5-p25 hyperactivity and tau hyperphosphorylation. J. Biol. Chem., 2010, 285(44), 34202-34212.
[] [PMID: 20720012]
Lau, L-F.; Ahlijanian, M.K. Role of cdk5 in the pathogenesis of Alzheimer’s disease. Neurosignals, 2003, 12(4-5), 209-214.
[] [PMID: 14673207]
Dixit, A.B.; Banerjee, J.; Tripathi, M.; Sarkar, C.; Chandra, P.S. Synaptic roles of cyclin-dependent kinase 5 & its implications in epilepsy. Indian J. Med. Res., 2017, 145(2), 179-188.
[PMID: 28639593]
Shah, K.; Lahiri, D.K. Cdk5 activity in the brain - multiple paths of regulation. J. Cell Sci., 2014, 127(Pt 11), 2391-2400.
[] [PMID: 24879856]
Schang, L.M. Cyclin-dependent kinases as cellular targets for antiviral drugs. J. Antimicrob. Chemother., 2002, 50(6), 779-792.
[] [PMID: 12460995]
Schang, L.M. Advances on cyclin-dependent kinases (CDKs) as novel targets for antiviral drugs. Curr. Drug Targets Infect. Disord., 2005, 5(1), 29-37.
[] [PMID: 15777196]
Wang, S.; Fischer, P.M. Cyclin-dependent kinase 9: a key transcriptional regulator and potential drug target in oncology, virology and cardiology. Trends Pharmacol. Sci., 2008, 29(6), 302-313.
[] [PMID: 18423896]
Nekhai, S.; Zhou, M.; Fernandez, A.; Lane, W.S.; Lamb, N.J.C.; Brady, J.; Kumar, A. HIV-1 Tat-associated RNA polymerase C terminal domain kinase, CDK2, phosphorylates CDK7 and stimulates Tat-mediated transcription. Biochem. J., 2002, 364(Pt 3), 649-657.
[] [PMID: 12049628]
Geyer, J.A.; Prigge, S.T.; Waters, N.C. Targeting malaria with specific CDK inhibitors. Biochim. Biophys. Acta, 2005, 1754(1-2), 160-170.
[] [PMID: 16185941]
Ward, P.; Equinet, L.; Packer, J.; Doerig, C. Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote. BMC Genomics, 2004, 5(1), 79.
[] [PMID: 15479470]
Hong, H.; Zeng, Y.; Jian, W.; Li, L.; Lin, L.; Mo, Y.; Liu, M.; Fang, S.; Xia, Y. CDK7 inhibition suppresses rheumatoid arthritis inflammation via blockage of NF-κB activation and IL-1β/IL-6 secretion. J. Cell. Mol. Med., 2018, 22(2), 1292-1301.
[PMID: 29083085]
U.S. Food & Drug Administration. FDA warns about rare but severe lung inflammation with Ibrance, Kisqali, and Verzenio for breast cancer. Available from:. ibrance-kisqali-and-verzenio-breast-cancer (Accessed on Feb 02, 2020).
Do, K.T.; Chau, N.; Wolanski, A.; Beardslee, B.; Hassinger, F.; Bhushan, K.; Pruitt-Thompson, S.; Scotton, A.; Frame, S.; Zheleva, D.I.; Blake, D.; Chiao, J.; Shapiro, G.I. Abstract CT037: Phase I safety, pharmacokinetic and pharmacodynamic study of CYC065, a cyclin dependent kinase inhibitor, in patients with advanced cancers (NCT02552953). Cancer Res., 2018, 78(13)(Suppl.), CT037-CT037.
Beaver, J.A.; Amiri-Kordestani, L.; Charlab, R.; Chen, W.; Palmby, T.; Tilley, A.; Zirkelbach, J.F.; Yu, J.; Liu, Q.; Zhao, L.; Crich, J.; Chen, X.H.; Hughes, M.; Bloomquist, E.; Tang, S.; Sridhara, R.; Kluetz, P.G.; Kim, G.; Ibrahim, A.; Pazdur, R.; Cortazar, P. FDA approval: Palbociclib for the treatment of postmenopausal patients with estrogen receptor-positive, her2-negative metastatic breast cancer. Clin. Cancer Res., 2015, 21(21), 4760-4766.
[] [PMID: 26324739]
Laderian, B.; Fojo, T. CDK4/6 Inhibition as a therapeutic strategy in breast cancer: palbociclib, ribociclib, and abemaciclib. Semin. Oncol., 2017, 44(6), 395-403.
[] [PMID: 29935901]
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.
[] [PMID: 30724426]
Bisi, J.E.; Sorrentino, J.A.; Roberts, P.J.; Tavares, F.X.; Strum, J.C. Preclinical characterization of G1T28: a novel CDK4/6 inhibitor for reduction of chemotherapy-induced myelosuppression. Mol. Cancer Ther., 2016, 15(5), 783-793.
[] [PMID: 26826116]
Bisi, J.E.; Sorrentino, J.A.; Jordan, J.L.; Darr, D.D.; Roberts, P.J.; Tavares, F.X.; Strum, J.C. Preclinical development of G1T38: A novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors. Oncotarget, 2017, 8(26), 42343-42358.
[] [PMID: 28418845]
Anon., New method for synthesis of 6-(difluoromethyl)-8-[(1R,2R)- 2-hydroxy2-methylcyclopentyl]-2-[1-(methylsulfonyl)-piperidin- 4-yl]aminopyrido[2,3-d]pyrimidin-7(8H)-one (PF-06873600). J. 2019, 19(7A), 1-3.
Behenna, D.C.; Chen, P.; Freeman-Cook, K.D.; Hoffman, R.L.; Jalaie, M.; Nagata, A.; Nair, S.K.; Ninkovic, S.; Ornelas, M.A.; Palmer, C.L.; Rui, E.Y. CDK2/4/6 inhibitors. U.S. Patent 20180044344A1, Feb 15th 2018.
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.
[PMID: 26207228]
Seftel, M.D.; Kuruvilla, J.; Kouroukis, T.; Banerji, V.; Fraser, G.; Crump, M.; Kumar, R.; Chalchal, H.I.; Salim, M.; Laister, R.C.; Crocker, S.; Gibson, S.B.; Toguchi, M.; Lyons, J.F.; Xu, H.; Powers, J.; Sederias, J.; Seymour, L.; Hay, A.E. The CDK inhibitor AT7519M in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. A Phase II study of the Canadian Cancer Trials Group. Leuk. Lymphoma, 2017, 58(6), 1358-1365.
[] [PMID: 27750483]
Kumar, S.K.; LaPlant, B.; Chng, W.J.; Zonder, J.; Callander, N.; Fonseca, R.; Fruth, B.; Roy, V.; Erlichman, C.; Stewart, A.K. Mayo Phase 2 Consortium. Dinaciclib, a novel CDK inhibitor, demonstrates encouraging single-agent activity in patients with relapsed multiple myeloma. Blood, 2015, 125(3), 443-448.
[] [PMID: 25395429]
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.
[] [PMID: 25816934]
Hirte, H.; Raghunadharao, D.; Baetz, T.; Hotte, S.; Rajappa, S.; Iacobucci, A.; Sharma, S.; Parikh, H.; Kulkarni, S.; Patil, S.; Padigaru, M.; Gaston, S. A phase 1 study of selective cyclin dependent kinase inhibitor P276-00 in patients with advanced refractory neoplasms. Mol. Cancer Ther., 2007, 6(11)(Suppl.), A112.
Joshi, K.S.; Rathos, M.J.; Joshi, R.D.; Sivakumar, M.; Mascarenhas, M.; Kamble, S.; Lal, B.; Sharma, S. In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00. Mol. Cancer Ther., 2007, 6(3), 918-925.
[] [PMID: 17363486]
Deep, A.; Marwaha, R.K.; Marwaha, M.G. Jyoti; Nandal, R.; Sharma, A.K. Flavopiridol as cyclin dependent kinase (CDK) inhibitor: a review. New J. Chem., 2018, 42(23), 18500-18507.
Besse, B.; Garassino, M.C.; Rajan, A.; Novello, S.; Mazieres, J.; Weiss, G.J.; Kocs, D.M.; Barnett, J.M.; Davite, C.; Crivori, P.; Giaccone, G. Efficacy of milciclib (PHA-848125AC), a pan-cyclin d-dependent kinase inhibitor, in two phase II studies with thymic carcinoma (TC) and B3 thymoma (B3T) patients. J. Clin. Oncol., 2018, 36(15_suppl), 8519-8519.
Ainscow, E.K.; Leishman, A.; Sullivan, E.; Li, B.; Gallagher, W.; Peall, A.; Clark, K.; Thomson, S.; Ali, S.; Coombes, R.C.; Bahl, A. Abstract 4834: CT7001: An orally bioavailable CDK7 inhibitor is apotential therapy for breast, small-cell lung and haematological cancers. Cancer Res., 2018, 78(13)(Suppl.), 4834.
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.
[] [PMID: 21860433]
U.S. National Library of Medicine Evaluation of safety and efficacy in bey1107 in monotherapy gemcitabine combination in patient with pancreatic cancer., (Feb 06, 2020).
Siemeister, G.; Lücking, U.; Wengner, A.M.; Lienau, P.; Steinke, W.; Schatz, C.; Mumberg, D.; Ziegelbauer, K. BAY 1000394, a novel cyclin-dependent kinase inhibitor, with potent antitumor activity in mono- and in combination treatment upon oral application. Mol. Cancer Ther., 2012, 11(10), 2265-2273.
[] [PMID: 22821149]
Lücking, U.; Scholz, A.; Lienau, P.; Siemeister, G.; Kosemund, D.; Bohlmann, R.; Briem, H.; Terebesi, I.; Meyer, K.; Prelle, K.; Denner, K.; Bömer, U.; Schäfer, M.; Eis, K.; Valencia, R.; Ince, S.; von Nussbaum, F.; Mumberg, D.; Ziegelbauer, K.; Klebl, B.; Choidas, A.; Nussbaumer, P.; Baumann, M.; Schultz-Fademrecht, C.; Rühter, G.; Eickhoff, J.; Brands, M. Identification of atuveciclib (BAY 1143572), the first highly selective, clinical ptefb/cdk9 inhibitor for the treatment of cancer. ChemMedChem, 2017, 12(21), 1776-1793.
[] [PMID: 28961375]
Luecking, U.T.; Scholz, A.; Kosemund, D.; Bohlmann, R.; Briem, H.; Lienau, P.; Siemeister, G.; Terebesi, I.; Meyer, K.; Prelle, K.; Valencia, R.; Ince, S.; Nussbaum, F.v.; Mumberg, D.; Ziegelbauer, K.; Brands, M. Abstract 984: Identification of potent and highly selective PTEFb inhibitor BAY 1251152 for the treatment of cancer: from p.o. to i.v. application via scaffold hops. Cancer Res., 2017, 77(13)(Suppl.), 984.
Walsby, E.; Lazenby, M.; Pepper, C.; Burnett, A.K. The cyclin dependent kinase inhibitor SNS-032 has single agent activity in AML cells and is highly synergistic with cytarabine. Leukemia, 2011, 25(3), 411-419.
[] [PMID: 21212792]
Gupta, S.; Jain, M.M.; Maru, A.; Nag, S.M.; Somani, N.; Mehta, A.O.; Kulkarni, S.; Acharya, S.A.; Dhobe, P.; Jadhav, N. A phase I study of selective cyclin dependent kinase inhibitor P1446A-05 administered on an intermittent schedule in patients with advanced refractory tumors. J. Clin. Oncol., 2012, 30(15_suppl), 3011-3011.
U.S. National Library of Medicine A phase I study of TQB3616 on tolerance and pharmacokinetics., Available from:. (Feb 05,2020).
Zhang, C.C.; Kephart, S.; McAlpine, I.; Nonomiya, J.; Higgins, J.; Arango, M.E.; Yan, Z.; Knighton, D.; Ferre, R.A.; Tikhe, J.; Verkhivker, G.; Xu, M.; Romines, W.; Palmer, C.; Park, J.; Reich, S.; Chong, W.; Li, L.; Los, G.; Lewis, C. AG-024322 is a potent and selective multi-targeted CDK inhibitor with broad spectrum anti-proliferative activity. Cancer Res., 2005, 65(9)(Suppl.), 1045.
[PMID: 15867387]
U.S. National Library of Medicine. A study of cs3002 in advanced solid tumors., Available from:. (Feb 05, 2020).
U.S. National Library of Medicine. A phase 1 study of hs-10342 in patients with advanced solid tumor., Available from:. (Feb 06, 2020).
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.
[] [PMID: 31064851]
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.
[] [PMID: 31699827]
Byth, K.F.; Thomas, A.; Hughes, G.; Forder, C.; McGregor, A.; Geh, C.; Oakes, S.; Green, C.; Walker, M.; Newcombe, N.; Green, S.; Growcott, J.; Barker, A.; Wilkinson, R.W. 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), 1856-1866.
[] [PMID: 19509270]
Rzymski, T.; Mikula, M.; Żyłkiewicz, E.; Dreas, A.; Wiklik, K.; Gołas, A.; Wójcik, K.; Masiejczyk, M.; Wróbel, A.; Dolata, I.; Kitlińska, A.; Statkiewicz, M.; Kuklinska, U.; Goryca, K.; Sapała, Ł.; Grochowska, A.; Cabaj, A.; Szajewska-Skuta, M.; Gabor- Worwa, E.; Kucwaj, K.; Białas, A.; Radzimierski, A.; Combik, M.; Woyciechowski, J.; Mikulski, M.; Windak, R.; Ostrowski, J.; Brzózka, K. SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains. Oncotarget, 2017, 8(20), 33779-33795.
[] [PMID: 28422713]
Grossman, S.A.; Ye, X.; Peereboom, D.; Rosenfeld, M.R.; Mikkelsen, T.; Supko, J.G.; Desideri, S. Adult Brain Tumor Consortium. Phase I study of terameprocol in patients with recurrent high-grade glioma. Neuro-oncol., 2012, 14(4), 511-517.
[] [PMID: 22323663]
Kim, W.; Haws, H.; Peterson, P.; Whatcott, C.J.; Weitman, S.; Warner, S.L.; Bearss, D.J.; Siddiqui-Jain, A. Abstract 5133: TP -1287, an oral prodrug of the cyclin-dependent kinase-9 inhibitor alvocidib. Cancer Res., 2017, 77(13)(Suppl.), 5133.
U.S. National Library of Medicine. Study of bcd-115 in women with er(+) her2(-) local advanced and metastatic breast cancer, Available from:. (Feb 05, 2020).
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.
[] [PMID: 20423997]
DePinto, W.; Chu, X-J.; Yin, X.; Smith, M.; Packman, K.; Goelzer, P.; Lovey, A.; Chen, Y.; Qian, H.; Hamid, R.; Xiang, Q.; Tovar, C.; Blain, R.; Nevins, T.; Higgins, B.; Luistro, L.; Kolinsky, K.; Felix, B.; Hussain, S.; Heimbrook, D. In vitro and in vivo activity of R547: a potent and selective cyclin-dependent kinase inhibitor currently in phase I clinical trials. Mol. Cancer Ther., 2006, 5(11), 2644-2658.
[] [PMID: 17121911]
U.S. National Library of Medicine. A phase I study of bpi-16350 in patients with advanced solid tumor., Available from:. (Feb 05, 2020).
Lin, S.; Zhao, X.; Li, T.; Zhang, H.; Tan, H.; Wang, X.; Jiang, L.; Liu, Y.; Sun, J.; Linghu, L.; Liu, Q.; Li, Z.; Zhang, W.; Wang, W. Abstract 4425: FCN-437: A novel, potent and selective oral inhibitor of CDK4/6 for the treatment of solid tumors. Cancer Res., 2019, 79(13)(Suppl.), 4425.
Wang, Y.; Zhi, Y.; Jin, Q.; Lu, S.; Lin, G.; Yuan, H.; Yang, T.; Wang, Z.; Yao, C.; Ling, J.; Guo, H.; Li, T.; Jin, J.; Li, B.; Zhang, L.; Chen, Y.; Lu, T. Discovery of 4-((7H-Pyrrolo[2,3-d]pyrimidin- 4-yl)amino)-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1Hpyrazole- 3-carboxamide (FN-1501), an FLT3- and CDK-kinase inhibitor with potentially high efficiency against acute myelocytic leukemia. J. Med. Chem., 2018, 61(4), 1499-1518.
[] [PMID: 29357250]
Richardson, G.E.; Vaishampayan, U.N.; Lin, L.; Bozon, V.; Hui, A.-M.; Williamson, S.K. A phase I clinical study to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of FN-1501 monotherapy in patients with advanced solid tumors. J. Clin. Oncol., 2019, 37(15_suppl), TPS3150-TPS3150.
Bharate, S.B.; Kumar, V.; Jain, S.K.; Mintoo, M.J.; Guru, S.K.; Nuthakki, V.K.; Sharma, M.; Bharate, S.S.; Gandhi, S.G.; Mondhe, D.M.; Bhushan, S.; Vishwakarma, R.A. Discovery and preclinical development of iiim-290, an orally active potent cyclin-dependent kinase inhibitor. J. Med. Chem., 2018, 61(4), 1664-1687.
[] [PMID: 29370702]
Hortobagyi, G.N.; Stemmer, S.M.; Burris, H.A.; Yap, Y-S.; Sonke, G.S.; Paluch-Shimon, S.; Campone, M.; Blackwell, K.L.; André, F.; Winer, E.P.; Janni, W.; Verma, S.; Conte, P.; Arteaga, C.L.; Cameron, D.A.; Petrakova, K.; Hart, L.L.; Villanueva, C.; Chan, A.; Jakobsen, E.; Nusch, A.; Burdaeva, O.; Grischke, E-M.; Alba, E.; Wist, E.; Marschner, N.; Favret, A.M.; Yardley, D.; Bachelot, T.; Tseng, L-M.; Blau, S.; Xuan, F.; Souami, F.; Miller, M.; Germa, C.; Hirawat, S.; O’Shaughnessy, J. Ribociclib as first-line therapy for hr-positive, advanced breast cancer. N. Engl. J. Med., 2016, 375(18), 1738-1748.
[] [PMID: 27717303]
Varella, L.; Eziokwu, A.S.; Jia, X.; Kruse, M.; Moore, H.C.F.; Budd, G.T.; Abraham, J.; Montero, A.J. Real-world clinical outcomes and toxicity in metastatic breast cancer patients treated with palbociclib and endocrine therapy. Breast Cancer Res. Treat., 2019, 176(2), 429-434.
[] [PMID: 30895534]
Kelland, L.R. Flavopiridol, the first cyclin-dependent kinase inhibitor to enter the clinic: current status. Expert Opin. Investig. Drugs, 2000, 9(12), 2903-2911.
[] [PMID: 11093360]
Turner, N.C.; Ro, J.; André, F.; Loi, S.; Verma, S.; Iwata, H.; Harbeck, N.; Loibl, S.; Huang Bartlett, C.; Zhang, K.; Giorgetti, C.; Randolph, S.; Koehler, M.; Cristofanilli, M. PALOMA3 study group. palbociclib in hormone-receptor-positive advanced breast cancer. N. Engl. J. Med., 2015, 373(3), 209-219.
[] [PMID: 26030518]
Goetz, M.P.; Toi, M.; Campone, M.; Sohn, J.; Paluch-Shimon, S.; Huober, J.; Park, I.H.; Trédan, O.; Chen, S-C.; Manso, L.; Freedman, O.C.; Garnica Jaliffe, G.; Forrester, T.; Frenzel, M.; Barriga, S.; Smith, I.C.; Bourayou, N.; Di Leo, A. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J. Clin. Oncol., 2017, 35(32), 3638-3646.
[] [PMID: 28968163]
Le Tourneau, C.; Faivre, S.; Laurence, V.; Delbaldo, C.; Vera, K.; Girre, V.; Chiao, J.; Armour, S.; Frame, S.; Green, S.R.; Gianella- Borradori, A.; Diéras, V.; Raymond, E. Phase I evaluation of seliciclib (R-roscovitine), a novel oral cyclin-dependent kinase inhibitor, in patients with advanced malignancies. Eur. J. Cancer, 2010, 46(18), 3243-3250.
[] [PMID: 20822897]
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.
[] [PMID: 25393368]
Mita, M.M.; Mita, A.C.; Moseley, J.L.; Poon, J.; Small, K.A.; Jou, Y-M.; Kirschmeier, P.; Zhang, D.; Zhu, Y.; Statkevich, P.; Sankhala, K.K.; Sarantopoulos, J.; Cleary, J.M.; Chirieac, L.R.; Rodig, S.J.; Bannerji, R.; Shapiro, G.I. Phase 1 safety, pharmacokinetic and pharmacodynamic study of the cyclin dependent kinase inhibitor dinaciclib administered every three weeks in patients with advanced malignancies. Br. J. Cancer, 2017, 117(9), 1258-1268.
[] [PMID: 28859059]
Luke, J.J.; D’Adamo, D.R.; Dickson, M.A.; Keohan, M.L.; Carvajal, R.D.; Maki, R.G.; de Stanchina, E.; Musi, E.; Singer, S.; Schwartz, G.K. The cyclin-dependent kinase inhibitor flavopiridol potentiates doxorubicin efficacy in advanced sarcomas: preclinical investigations and results of a phase I dose-escalation clinical trial. Clin. Cancer Res., 2012, 18(9), 2638-2647.
[] [PMID: 22374332]
Roboz, G.J.; Khoury, H.J.; Shammo, J.M.; Syto, M.; Burrows, F.; Zaknoen, S.L.; Jabbour, E. Phase I dose escalation study of TG02 in patients with advanced hematologic malignancies. J. Clin. Oncol., 2012, 30(15_suppl), 6577-6577.
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, JC. Phase I dose-escalation studies of roniciclib, a pan-cyclin dependent kinase inhibitor, in advanced malignancies. Br. J. Cancer, 2017, 116(12), 1505-1512.
[] [PMID: 28463960]
Blachly, J.S.; Byrd, J.C. Emerging drug profile: cyclin-dependent kinase inhibitors. Leuk. Lymphoma, 2013, 54(10), 2133-2143.
[] [PMID: 23488658]
Legraverend, M.; Tunnah, P.; Noble, M.; Ducrot, P.; Ludwig, O.; Grierson, D.S.; Leost, M.; Meijer, L.; Endicott, J. Cyclin-dependent kinase inhibition by new C-2 alkynylated purine derivatives and molecular structure of a CDK2-inhibitor complex. J. Med. Chem., 2000, 43(7), 1282-1292.
[] [PMID: 10753466]
Ibrahim, D.A.; El-Metwally, A.M. Design, synthesis, and biological evaluation of novel pyrimidine derivatives as CDK2 inhibitors. Eur. J. Med. Chem., 2010, 45(3), 1158-1166.
[] [PMID: 20045222]
Jacquemard, U.; Dias, N.; Lansiaux, A.; Bailly, C.; Logé, C.; Robert, J-M.; Lozach, O.; Meijer, L.; Mérour, J-Y.; Routier, S. Synthesis of 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5- phenyl]pyridine derivatives as CDK inhibitors and cytotoxic agents. Bioorg. Med. Chem., 2008, 16(9), 4932-4953.
[] [PMID: 18439832]
Sanchez-Martinez, C.; Shih, C.; Zhu, G.; Li, T.; Brooks, H.B.; Patel, B.K.; Schultz, R.M.; DeHahn, T.B.; Spencer, C.D.; Watkins, S.A.; Ogg, C.A.; Considine, E.; Dempsey, J.A.; Zhang, F. Studies on cyclin-dependent kinase inhibitors: indolo-[2,3-a]pyrrolo[3,4- c]carbazoles versus bis-indolylmaleimides. Bioorg. Med. Chem. Lett., 2003, 13(21), 3841-3846.
[] [PMID: 14552792]
Dermatakis, A.; Luk, K-C.; DePinto, W. Synthesis of potent oxindole CDK2 inhibitors. Bioorg. Med. Chem., 2003, 11(8), 1873-1881.
[] [PMID: 12659774]
Misra, R.N.; Xiao, H.Y.; Kim, K.S.; Lu, S.; Han, W-C.; Barbosa, S.A.; Hunt, J.T.; Rawlins, D.B.; Shan, W.; Ahmed, S.Z.N.; Qian, L.; Chen, B.C.; Zhao, R.; Bednarz, M.S.; Kellar, K.A.; Mulheron, J.G.; Batorsky, R.; Roongta, U.; Kamath, A.; Marathe, P.; Ranadive, S.A.; Sack, J.S.; Tokarski, J.S.; Pavletich, N.P.; Lee, F.Y.; Webster, K.R.; Kimball, S.D. N-(cycloalkylamino)acyl-2- aminothiazole inhibitors of cyclin-dependent kinase 2. N-[5- [[[5-(1,1-dimethylethyl)-2-oxazolyl]methyl]thio]-2-thiazolyl]-4- piperidinecarboxamide (BMS-387032), a highly efficacious and selective antitumor agent. J. Med. Chem., 2004, 47(7), 1719-1728.
[] [PMID: 15027863]
Wang, S.; Wood, G.; Meades, C.; Griffiths, G.; Midgley, C.; McNae, I.; McInnes, C.; Anderson, S.; Jackson, W.; Mezna, M.; Yuill, R.; Walkinshaw, M.; Fischer, P.M. Synthesis and biological activity of 2-anilino-4-(1H-pyrrol-3-yl) pyrimidine CDK inhibitors. Bioorg. Med. Chem. Lett., 2004, 14(16), 4237-4240.
[] [PMID: 15261277]
Shao, H.; Shi, S.; Foley, D.W.; Lam, F.; Abbas, A.Y.; Liu, X.; Huang, S.; Jiang, X.; Baharin, N.; Fischer, P.M.; Wang, S. Synthesis, structure-activity relationship and biological evaluation of 2,4,5-trisubstituted pyrimidine CDK inhibitors as potential anti tumour agents. Eur. J. Med. Chem., 2013, 70, 447-455.
[] [PMID: 24185375]
Wang, S.; Meades, C.; Wood, G.; Osnowski, A.; Anderson, S.; Yuill, R.; Thomas, M.; Mezna, M.; Jackson, W.; Midgley, C.; Griffiths, G.; Fleming, I.; Green, S.; McNae, I.; Wu, S-Y.; McInnes, C.; Zheleva, D.; Walkinshaw, M.D.; Fischer, P.M. 2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity. J. Med. Chem., 2004, 47(7), 1662-1675.
[] [PMID: 15027857]
Wang, Y.; Chen, X.; Yan, Y.; Zhu, X.; Liu, M.; Liu, X. Discovery and SARs of 5-Chloro-N4-phenyl-N2-(pyridin-2-yl)pyrimidine-2,4- diamine Derivatives as Oral Available and Dual CDK 6 and 9 Inhibitors with Potent Antitumor Activity. J. Med. Chem., 2020, 63(6), 3327-3347.
[] [PMID: 32129996]
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.
[] [PMID: 21080703]
Nie, Z.; Perretta, C.; Erickson, P.; Margosiak, S.; Lu, J.; Averill, A.; Almassy, R.; Chu, S. Structure-based design and synthesis of novel macrocyclic pyrazolo[1,5-a] [1,3,5]triazine compounds as potent inhibitors of protein kinase CK2 and their anticancer activities. Bioorg. Med. Chem. Lett., 2008, 18(2), 619-623.
[] [PMID: 18055206]
Lukasik, P.M.; Elabar, S.; Lam, F.; Shao, H.; Liu, X.; Abbas, A.Y.; Wang, S. Synthesis and biological evaluation of imidazo[4,5- b]pyridine and 4-heteroaryl-pyrimidine derivatives as anti-cancer agents. Eur. J. Med. Chem., 2012, 57, 311-322.
[] [PMID: 23085105]
Moravcová, D.; Kryštof, V.; Havlícek, L.; Moravec, J.; Lenobel, R.; Strnad, M. Pyrazolo[4,3-d]pyrimidines as new generation of cyclin dependent kinase inhibitors. Bioorg. Med. Chem. Lett., 2003, 13(18), 2989-2992.
[] [PMID: 12941318]
Dwyer, M.P.; Paruch, K.; Alvarez, C.; Doll, R.J.; Keertikar, K.; Duca, J.; Fischmann, T.O.; Hruza, A.; Madison, V.; Lees, E.; Parry, D.; Seghezzi, W.; Sgambellone, N.; Shanahan, F.; Wiswell, D.; Guzi, T.J. Versatile templates for the development of novel kinase inhibitors: Discovery of novel CDK inhibitors. Bioorg. Med. Chem. Lett., 2007, 17(22), 6216-6219.
[] [PMID: 17904366]
Wang, Y.; Chen, Y.; Cheng, X.; Zhang, K.; Wang, H.; Liu, B.; Wang, J. Design, synthesis and biological evaluation of pyrimidine derivatives as novel CDK2 inhibitors that induce apoptosis and cell cycle arrest in breast cancer cells. Bioorg. Med. Chem., 2018, 26(12), 3491-3501.
[] [PMID: 29853338]
Gray, N.; Détivaud, L.; Doerig, C.; Meijer, L. ATP-site directed inhibitors of cyclin-dependent kinases. Curr. Med. Chem., 1999, 6(9), 859-875.
[PMID: 10495356]
Trova, M.P.; Barnes, K.D.; Barford, C.; Benanti, T.; Bielaska, M.; Burry, L.; Lehman, J.M.; Murphy, C.; O’Grady, H.; Peace, D.; Salamone, S.; Smith, J.; Snider, P.; Toporowski, J.; Tregay, S.; Wilson, A.; Wyle, M.; Zheng, X.; Friedrich, T.D. Biaryl purine derivatives as potent antiproliferative agents: inhibitors of cyclin dependent kinases. Part I. Bioorg. Med. Chem. Lett., 2009, 19(23), 6608-6612.
[] [PMID: 19846305]
Trova, M.P.; Barnes, K.D.; Alicea, L.; Benanti, T.; Bielaska, M.; Bilotta, J.; Bliss, B.; Duong, T.N.; Haydar, S.; Herr, R.J.; Hui, Y.; Johnson, M.; Lehman, J.M.; Peace, D.; Rainka, M.; Snider, P.; Salamone, S.; Tregay, S.; Zheng, X.; Friedrich, T.D. Heterobiaryl purine derivatives as potent antiproliferative agents: inhibitors of cyclin dependent kinases. Part II. Bioorg. Med. Chem. Lett., 2009, 19(23), 6613-6617.
[] [PMID: 19854650]
Moravec, J.; Kryštof, V.; Hanuš, J.; Havlícek, L.; Moravcová, D.; Fuksová, K.; Kuzma, M.; Lenobel, R.; Otyepka, M.; Strnad, M. 2,6,8,9-tetrasubstituted purines as new CDK1 inhibitors. Bioorg. Med. Chem. Lett., 2003, 13(18), 2993-2996.
[] [PMID: 12941319]
Vandromme, L.; Piguel, S.; Lozach, O.; Meijer, L.; Legraverend, M.; Grierson, D.S. Suzuki-type Pd(0) coupling reactions in the synthesis of 2-arylpurines as Cdk inhibitors. Bioorg. Med. Chem. Lett., 2006, 16(12), 3144-3146.
[] [PMID: 16616489]
Sun, J.; Lv, X-H.; Qiu, H-Y.; Wang, Y-T.; Du, Q-R.; Li, D-D.; Yang, Y-H.; Zhu, H-L. Synthesis, biological evaluation and molecular docking studies of pyrazole derivatives coupling with a thiourea moiety as novel CDKs inhibitors. Eur. J. Med. Chem., 2013, 68, 1-9.
[] [PMID: 23933045]
Lin, R.; Chiu, G.; Yu, Y.; Connolly, P.J.; Li, S.; Lu, Y.; Adams, M.; Fuentes-Pesquera, A.R.; Emanuel, S.L.; Greenberger, L.M. Design, synthesis, and evaluation of 3,4-disubstituted pyrazole analogues as anti-tumor CDK inhibitors. Bioorg. Med. Chem. Lett., 2007, 17(16), 4557-4561.
[] [PMID: 17574416]
Jorda, R.; Schütznerová, E.; Cankař, P.; Brychtová, V.; Navrátilová, J.; Kryštof, V. Novel arylazopyrazole inhibitors of cyclin-dependent kinases. Bioorg. Med. Chem., 2015, 23(9), 1975-1981.
[] [PMID: 25835357]
Kryštof, V.; Cankař, P.; Frysová, I.; Slouka, J.; Kontopidis, G.; Dzubák, P.; Hajdúch, M.; Srovnal, J.; de Azevedo, W.F., Jr; Orság, M.; Paprskárová, M.; Rolcík, J.; Látr, A.; Fischer, P.M.; Strnad, M. 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(22), 6500-6509.
[] [PMID: 17064068]
Havlicek, L.; Fuksova, K.; Krystof, V.; Orsag, M.; Vojtesek, B.; Strnad, M. 8-Azapurines as new inhibitors of cyclin-dependent kinases. Bioorg. Med. Chem., 2005, 13(18), 5399-5407.
[] [PMID: 15993080]
Trova, M.P. 6-Substituted biaryl purine derivatives as potent cyclin/CDK inhibitors and antiproliferative agents. U.S. Patent 6,627,633, September 23, 2003.
Akué-Gédu, R.; Letribot, B.; Saugues, E.; Debiton, E.; Anizon, F.; Moreau, P. Kinase inhibitory potencies and in vitro antiproliferative activities of N-10 substituted pyrrolo[2,3-a]carbazole derivatives. Bioorg. Med. Chem. Lett., 2012, 22(11), 3807-3809.
[] [PMID: 22543026]
Wyatt, P.G.; Woodhead, A.J.; Berdini, V.; Boulstridge, J.A.; Carr, M.G.; Cross, D.M.; Davis, D.J.; Devine, L.A.; Early, T.R.; Feltell, R.E.; Lewis, E.J.; McMenamin, R.L.; Navarro, E.F.; O’Brien, M.A.; O’Reilly, M.; Reule, M.; Saxty, G.; Seavers, L.C.; Smith, D.M.; Squires, M.S.; Trewartha, G.; Walker, M.T.; Woolford, A.J. Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)- 1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure based drug design. J. Med. Chem., 2008, 51(16), 4986-4999.
[] [PMID: 18656911]
Brasca, M.G.; Albanese, C.; Amici, R.; Ballinari, D.; Corti, L.; Croci, V.; Fancelli, D.; Fiorentini, F.; Nesi, M.; Orsini, P.; Orzi, F.; Pastori, W.; Perrone, E.; Pesenti, E.; Pevarello, P.; Riccardi-Sirtori, F.; Roletto, F.; Roussel, P.; Varasi, M.; Vulpetti, A.; Mercurio, C. 6-Substituted pyrrolo[3,4-c]pyrazoles: an improved class of CDK2 inhibitors. ChemMedChem, 2007, 2(6), 841-852.
[] [PMID: 17450625]
Brasca, M.G.; Albanese, C.; Alzani, R.; Amici, R.; Avanzi, N.; Ballinari, D.; Bischoff, J.; Borghi, D.; Casale, E.; Croci, V.; Fiorentini, F.; Isacchi, A.; Mercurio, C.; Nesi, M.; Orsini, P.; Pastori, W.; Pesenti, E.; Pevarello, P.; Roussel, P.; Varasi, M.; Volpi, D.; Vulpetti, A.; Ciomei, M. Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing. Bioorg. Med. Chem., 2010, 18(5), 1844-1853.
[] [PMID: 20153204]
Pevarello, P.; Fancelli, D.; Vulpetti, A.; Amici, R.; Villa, M.; Pittalà, V.; Vianello, P.; Cameron, A.; Ciomei, M.; Mercurio, C.; Bischoff, J.R.; Roletto, F.; Varasi, M.; Brasca, M.G. 3-Amino-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazoles: a new class of CDK2 inhibitors. Bioorg. Med. Chem. Lett., 2006, 16(4), 1084-1090.
[] [PMID: 16290148]
Bai, X-G.; Yu, D-K.; Wang, J-X.; Zhang, H.; He, H-W.; Shao, RG.; Li, X-M.; Wang, Y-C. Design, synthesis and anticancer activity of 1-acyl-3-amino-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives. Bioorg. Med. Chem. Lett., 2012, 22(22), 6947-6951.
[] [PMID: 23036956]
Engler, T.A.; Furness, K.; Malhotra, S.; Sanchez-Martinez, C.; Shih, C.; Xie, W.; Zhu, G.; Zhou, X.; Conner, S.; Faul, M.M.; Sullivan, K.A.; Kolis, S.P.; Brooks, H.B.; Patel, B.; Schultz, R.M.; DeHahn, T.B.; Kirmani, K.; Spencer, C.D.; Watkins, S.A.; Considine, E.L.; Dempsey, J.A.; Ogg, C.A.; Stamm, N.B.; Anderson, B.D.; Campbell, R.M.; Vasudevan, V.; Lytle, M.L. Novel, potent and selective cyclin D1/CDK4 inhibitors: indolo[6,7- a]pyrrolo[3,4-c]carbazoles. Bioorg. Med. Chem. Lett., 2003, 13(14), 2261-2267.
[] [PMID: 12824014]
Fousteris, M.A.; Papakyriakou, A.; Koutsourea, A.; Manioudaki, M.; Lampropoulou, E.; Papadimitriou, E.; Spyroulias, G.A.; Nikolaropoulos, S.S. Pyrrolo[2,3-a]carbazoles as potential cyclin dependent kinase 1 (CDK1) Inhibitors. Synthesis, biological evaluation, and binding mode through docking simulations. J. Med. Chem., 2008, 51(4), 1048-1052.
[] [PMID: 18232654]
Zhu, G.; Conner, S.; Zhou, X.; Shih, C.; Brooks, H.B.; Considine, E.; Dempsey, J.A.; Ogg, C.; Patel, B.; Schultz, R.M.; Spencer, C.D.; Teicher, B.; Watkins, S.A. Synthesis of quinolinyl/isoquinolinyl[a]pyrrolo [3,4-c] carbazoles as cyclin D1/CDK4 inhibitors. Bioorg. Med. Chem. Lett., 2003, 13(7), 1231-1235.
[] [PMID: 12657252]
Sanchez-Martinez, C.; Shih, C.; Faul, M.M.; Zhu, G.; Paal, M.; Somoza, C.; Li, T.; Kumrich, C.A.; Winneroski, L.L.; Xun, Z.; Brooks, H.B.; Patel, B.K.; Schultz, R.M.; DeHahn, T.B.; Spencer, C.D.; Watkins, S.A.; Considine, E.; Dempsey, J.A.; Ogg, C.A.; Campbell, R.M.; Anderson, B.A.; Wagner, J. Aryl[a]pyrrolo[3,4- c]carbazoles as selective cyclin D1-CDK4 inhibitors. Bioorg. Med. Chem. Lett., 2003, 13(21), 3835-3839.
[] [PMID: 14552791]
Faul, M.M.; Engler, T.A.; Sullivan, K.A.; Grutsch, J.L.; Clayton, M.T.; Martinelli, M.J.; Pawlak, J.M.; LeTourneau, M.; Coffey, D.S.; Pedersen, S.W.; Kolis, S.P.; Furness, K.; Malhotra, S.; Alawar, R.S.; Ray, J.E. Synthetic approaches to indolo[6,7- a]pyrrolo[3,4-c]carbazoles: potent cyclin D1/CDK4 inhibitors. J. Org. Chem., 2004, 69(9), 2967-2975.
[] [PMID: 15104433]
Veselý, J.; Havliček, L.; Strnad, M.; Blow, J.J.; Donella-Deana, A.; Pinna, L.; Letham, D.S.; Kato, J.; Detivaud, L.; Leclerc, S.; Meijer, L. Inhibition of cyclin-dependent kinases by purine analogues. Eur. J. Biochem., 1994, 224(2), 771-786.
[] [PMID: 7925396]
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.
[] [PMID: 9030781]
Chang, Y-T.; Gray, N.S.; Rosania, G.R.; Sutherlin, D.P.; Kwon, S.; Norman, T.C.; Sarohia, R.; Leost, M.; Meijer, L.; Schultz, P.G. Synthesis and application of functionally diverse 2,6,9-trisubstituted purine libraries as CDK inhibitors. Chem. Biol., 1999, 6(6), 361-375.
[] [PMID: 10375538]
Jain, S.K.; Bharate, S.B.; Vishwakarma, R.A. Cyclin-dependent kinase inhibition by flavoalkaloids. Mini Rev. Med. Chem., 2012, 12(7), 632-649.
[] [PMID: 22512551]
U.S. National Library of Medicine Available from:. (Feb 02, 2020).
Meijer, L.; Thunnissen, A.M.; White, A.W.; Garnier, M.; Nikolic, M.; Tsai, L.H.; Walter, J.; Cleverley, K.E.; Salinas, P.C.; Wu, Y.Z.; Biernat, J.; Mandelkow, E.M.; Kim, S.H.; Pettit, G.R. Inhibition of cyclin-dependent kinases, GSK-3β and CK1 by hymenialdisine, a marine sponge constituent. Chem. Biol., 2000, 7(1), 51-63.
[] [PMID: 10662688]
Soni, R.; Muller, L.; Furet, P.; Schoepfer, J.; Stephan, C.; Zumstein-Mecker, S.; Fretz, H.; Chaudhuri, B. Inhibition of cyclin-dependent kinase 4 (Cdk4) by fascaplysin, a marine natural product. Biochem. Biophys. Res. Commun., 2000, 275(3), 877-884.
[] [PMID: 10973815]
Bharate, S.B.; Manda, S.; Mupparapu, N.; Battini, N.; Vishwakarma, R.A. Chemistry and biology of fascaplysin, a potent marine-derived CDK-4 inhibitor. Mini Rev. Med. Chem., 2012, 12(7), 650-664.
[] [PMID: 22512549]
Gompel, M.; Leost, M.; De Kier Joffe, E.B.; Puricelli, L.; Franco, L.H.; Palermo, J.; Meijer, L. Meridianins, a new family of protein kinase inhibitors isolated from the ascidian Aplidium meridianum. Bioorg. Med. Chem. Lett., 2004, 14(7), 1703-1707.
[] [PMID: 15026054]
Bharate, S.B.; Yadav, R.R.; Battula, S.; Vishwakarma, R.A. Meridianins: marine-derived potent kinase inhibitors. Mini Rev. Med. Chem., 2012, 12(7), 618-631.
[] [PMID: 22512550]
Simone, M.; Erba, E.; Damia, G.; Vikhanskaya, F.; Di Francesco, A.M.; Riccardi, R.; Bailly, C.; Cuevas, C.; Fernandez Sousa-Faro, J.M.; D’Incalci, M. Variolin B and its derivate deoxy-variolin B: new marine natural compounds with cyclin-dependent kinase inhibitor activity. Eur. J. Cancer, 2005, 41(15), 2366-2377.
[] [PMID: 16181779]
Kobayashi, J.i.; Suzuki, M.; Tsuda, M. Konbu’acidin A, a new bromopyrrole alkaloid with cdk4 inhibitory activity from Hymeniacidon sponge. Tetrahedron, 1997, 53(46), 15681-15684.
Tamaoki, T. Use and specificity of staurosporine, UCN-O1, and calphostin C as protein kinase inhibitors. Methods Enzymol; Academic Press: Cambridge, 1991, Vol. 201, pp. 340-347.
Tamaoki, T.; Nomoto, H.; Takahashi, I.; Kato, Y.; Morimoto, M.; Tomita, F. Staurosporine, a potent inhibitor of phospholipid/Ca++dependent protein kinase. Biochem. Biophys. Res. Commun., 1986, 135(2), 397-402.
[] [PMID: 3457562]
Gadbois, D.M.; Hamaguchi, J.R.; Swank, R.A.; Bradbury, E.M. Staurosporine is a potent inhibitor of p34cdc2 and p34cdc2-like kinases. Biochem. Biophys. Res. Commun., 1992, 184(1), 80-85.
[] [PMID: 1567459]
Gadbois, D.M.; Crissman, H.A.; Tobey, R.A.; Bradbury, E.M. Multiple kinase arrest points in the G1 phase of nontransformed mammalian cells are absent in transformed cells. Proc. Natl. Acad. Sci. USA, 1992, 89(18), 8626-8630.
[] [PMID: 1528872]
Gali-Muhtasib, H.; Bakkar, N. Modulating cell cycle: current applications and prospects for future drug development. Curr. Cancer Drug Targets, 2002, 2(4), 309-336.
[] [PMID: 12470209]
Flaherty, K.T.; Lorusso, P.M.; Demichele, A.; Abramson, V.G.; Courtney, R.; Randolph, S.S.; Shaik, M.N.; Wilner, K.D.; O’Dwyer, P.J.; Schwartz, G.K.; Phase, I. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin. Cancer Res., 2012, 18(2), 568-576.
[] [PMID: 22090362]
Lynce, F.; Shajahan-Haq, A.N.; Swain, S.M. CDK4/6 inhibitors in breast cancer therapy: Current practice and future opportunities. Pharmacol. Ther., 2018, 191, 65-73.
[] [PMID: 29933034]
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.
[] [PMID: 18054800]
Malumbres, M.; Barbacid, M. Is Cyclin D1-CDK4 kinase a bona fide cancer target? Cancer Cell, 2006, 9(1), 2-4.
[] [PMID: 16413464]
Kwong, L.N.; Costello, J.C.; Liu, H.; Jiang, S.; Helms, T.L.; Langsdorf, A.E.; Jakubosky, D.; Genovese, G.; Muller, F.L.; Jeong, J.H.; Bender, R.P.; Chu, G.C.; Flaherty, K.T.; Wargo, J.A.; Collins, J.J.; Chin, L. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat. Med., 2012, 18(10), 1503-1510.
[] [PMID: 22983396]
Franco, J.; Witkiewicz, A.K.; Knudsen, E.S. CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget, 2014, 5(15), 6512-6525.
[] [PMID: 25156567]
Heilmann, A.M.; Perera, R.M.; Ecker, V.; Nicolay, B.N.; Bardeesy, N.; Benes, C.H.; Dyson, N.J. CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers. Cancer Res., 2014, 74(14), 3947-3958.
[] [PMID: 24986516]
Cortés, J.; Im, S.A.; Holgado, E.; Perez-Garcia, J.M.; Schmid, P.; Chavez-MacGregor, M. The next era of treatment for hormone receptor-positive, HER2-negative advanced breast cancer: Triplet combination-based endocrine therapies. Cancer Treat. Rev., 2017, 61, 53-60.
[] [PMID: 29100169]
Whittaker, S.; Madani, D.; Joshi, S.; Chung, S.A.; Johns, T.; Day, B.; Khasraw, M.; McDonald, K.L. Combination of palbociclib and radiotherapy for glioblastoma. Cell Death Discov., 2017, 3(1), 17033.
[] [PMID: 28690875]

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