Discovery of 8-cyclopentyl-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-7- oxo-7,8-dihydro-pyrido[2,3- d ]pyrimidine-6-carbonitrile (7x) as a potent inhibitor of cyclin-dependent kinase 4 (CDK4) and AMPK-related kinase 5 (ARK5)

Journal of Medicinal Chemistry

Volumn 57, Issue 3, 2014, Pages 578-599

  Reddy, M V Ramana ^a   Akula, Balireddy ^b   Cosenza, Stephen C ^a   Athuluridivakar, Saikrishna ^a   Mallireddigari, Muralidhar R ^b   Pallela, Venkat R ^b   Billa, Vinay K ^a   Subbaiah, D R C Venkata ^a   Bharathi, E Vijaya ^a   Vasquez Del Carpio, Rodrigo ^a   Padgaonkar, Amol ^a   Baker, Stacey J ^a   Reddy, E Premkumar ^a  

^a MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^b Onconova Therapeutics Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; CELL CYCLE; CELL LINE, TUMOR; CYCLIN-DEPENDENT KINASE 4; DRUG SCREENING ASSAYS, ANTITUMOR; FEMALE; HETEROGRAFTS; HUMANS; MICE; MICE, NUDE; MOLECULAR DOCKING SIMULATION; NEOPLASM TRANSPLANTATION; PROTEIN KINASES; PYRIDINES; PYRIMIDINES; REPRESSOR PROTEINS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84894044278     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm401073p     Document Type: Article

References (62)

1. Malumbres, M.; Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm Nature Rev. Cancer 2009, 9, 153-166
2. Graña, X.; Reddy, E. P. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs) Oncogene 1995, 11, 211-219
3. Hunter, T. Oncoprotein networks Cell 1997, 88, 333-346
4. Morgan, D. O. Cyclin-dependent kinases: engines, clocks, and microprocessors Ann. Rev. Cell Dev. Biol. 1997, 13, 261-291
5. Malumbres, M.; Barbacid, M. To cycle or not to cycle: a critical decision in cancer Nature Rev. Cancer 2001, 1, 222-231
6. Baker, S. J.; Reddy, E. P. CDK4 a key player in the cell cycle, development, and cancer Genes Cancer 2012, 3, 658-669
7. Dyson, N. The regulation of E2F by pRB-family proteins Genes Dev. 1998, 12, 2245-2262
8. Harbour, J. W.; Dean, D. C. The Rb/E2F pathway: expanding roles and emerging paradigms Genes Dev. 2000, 14, 2393-2409
9. Deshpande, A.; Sicinski, P.; Hinds, P. W. Cyclins and cdks in development and cancer: a perspective Oncogene 2005, 24, 2909-2915
10. Graf, F.; Mosch, B.; Koehler, L.; Bergmann, R.; Wuest, F.; Pietzsch, J. Cyclin-dependent kinase 4/6 (Cdk4/6) inhibitors: perspectives in cancer therapy and imaging Mini-Rev. Med. Chem. 2010, 10, 527-539
11. Wolfel, 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, 1281-1284
12. Zuo, L.; Weger, J.; Yang, Q.; Goldstein, A. M.; Tucker, M. A.; Walker, G. J.; Hayward, N.; Dracopoli, N. C. Germline mutations in the p16INK4a binding domain of CDK4 in familial melanoma Nature Genet. 1996, 12, 97-99
13. Ortega, S.; Malumbres, M.; Barbacid, M. Cyclin D-dependent kinases, INK4 inhibitors and cancer Biochim. Biophys. Acta 2002, 1602, 73-87
14. Rane, S. G.; Dubus, P. D.; Mettus, R. V.; Galbreath, E. J.; Boden, G.; Reddy, E. P.; Barbacid, M. Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in beta-islet cell hyperplasia Nature Genet. 1999, 22, 44-52
15. Tsutsui, T.; Hesabi, B.; Moons, D. S.; Pandolfi, P. P.; Hansel, K. S.; Koff, A.; Kiyokawa, H. Targeted disruption of CDK4 delays cell cycle entry with enhanced p27(Kip1) activity Mol. Cell. Biol. 1999, 19, 7011-7019
16. Reddy, H. K.; Mettus, R. V.; Rane, S. G.; Graña, X.; Litvin, J.; Reddy, E. P. Cyclin-dependent kinase 4 expression is essential for neu-induced breast tumorigenesis Cancer Res. 2005, 65, 10174-10178
17. Reddy, H. K.; Graña, X.; Dhanasekaran, D. N.; Litvin, J.; Reddy, E. P. Requirement of Cdk4 for v-Haras-induced breast tumorigenesis and activation of the v-ras-induced senescence program by the R24C mutation Genes Cancer 2010, 1, 69-80
18. Carlson, B. A.; Dubay, M. M.; Sausville, E. A.; Brizuela, L.; Worland, P. J. Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells Cancer Res. 1996, 56, 2973-2978
19. McClue, S. J.; Blake, D.; Clarke, R.; Cowan, A.; Cummings, L.; Fischer, P. M.; MacKenzie, M.; Melville, J.; Stewart, K.; Wang, S.; Zhelev, N.; Zheleva, D.; Lane, D. P. In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine) Int. J. Cancer 2002, 102, 463-468
20. Ullah, Z.; Lee, C. Y.; Depamphilis, M. L. Cip/Kip cyclin-dependent protein kinase inhibitors and the road to polyploidy Cell Div. 2009, 4, 10
21. Musgrove, E. A.; Caldon, C. E.; Barraclough, J.; Stone, A.; Sutherland, R. L. Cyclin D as a therapeutic target in cancer Nature Rev. Cancer 2011, 11, 558-572
22. Lapenna, S.; Giordano, A. Cell cycle kinases as therapeutic targets for cancer Nature Rev. Drug Discovery 2009, 8, 547-566
23. Shapiro, G. I. Cyclin-dependent kinase pathways as targets for cancer treatment J. Clin. Oncol. 2006, 24, 1770-1783
24. Lane, M. E.; Yu, B.; Rice, A.; Lipson, K. E.; Liang, C.; Sun, L.; Tang, C.; McMahon, G.; Pestell, R. G.; Wadler, S. A novel cdk2-selective inhibitor, SU9516, induces apoptosis in colon carcinoma cells Canccer Res. 2001, 61, 6170-6177
25. Soni, R.; O'Reilly, T.; Furet, P.; Muller, L.; Stephan, C.; Zumstein-Mecker, S.; Fretz, H.; Fabbro, D.; Chaudhuri, B. Selective in vivo and in vitro effects of a small molecule inhibitor of cyclin-dependent kinase 4 J. Natl. Cancer Inst. 2001, 93, 436-446
26. Honma, T.; Hayaski, K.; Aoyama, T.; Hashimoto, N.; Machida, T.; Fukasawa, K.; wama, T.; Ikeura, C.; Ikuta, M.; Suzuki-Takahashi, I.; Iwasawa, Y.; Hayama, T.; Nishimura, S.; Morishima, H. Structure-Based Generation of a New Class of Potent Cdk4 Inhibitors: New de Novo Design Strategy and Library Design J. Med. Chem. 2001, 44, 4615-4627
27. Honma, T.; Yoshizumi, T.; Hashimoto, N.; Hayashi, K.; Kawanishi, N.; Fukasawa, K.; Takaki, T.; Ikeura, C.; Ikuta, M.; Suzuki-Takahashi, I.; Hayama, T.; Nishimura, S.; Morishima, H. A novel approach for the development of selective Cdk4 inhibitors: library design based on locations of Cdk4 specific amino acid residues J. Med. Chem. 2001, 44, 4628-4640
28. Verdaguer, E.; Jordà, E. G.; Canudas, A. M.; Jiménez, A.; Sureda, F. X.; Rimbau, V.; Pubill, D.; Escubedo, E.; Camarasa, J.; Pallàs, M.; Camins, A. 3-Amino thioacridone, a selective cyclin-dependent kinase 4 inhibitor, attenuates kainic acid-induced apoptosis in neurons Neuroscience 2003, 120, 599-603
29. Misra, R. N.; Xiao, H.; Kim, K. S.; Lu, S.; Han, W.-C.; Barbosa, S. A.; Hunt, J. T.; Rawlins, D. B.; Shan, W.; Ahmed, S. Z.; 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. F.; Webster, K. R.; Kimball, S. D. N -(Cycloalkylmino) 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, 1719-1728
30. Zhu, G.; Conner, S. E.; Zhou, X.; Shih, C.; Li, T.; Anderson, B. D.; Brooks, H. B.; Campbell, R. M.; Considine, E.; Dempsey, J. A.; Faul, M. M.; Ogg, C.; Patel, B.; Schultz, R. M.; Spencer, C. D.; Teicher, B.; Watkins, S. A. Synthesis, structure-activity relationship, and biological studies of indolocarbazoles as potent cyclin D1-CDK4 inhibitors J. Med. Chem. 2003, 46, 2027-2030
31. Toogood, P. L.; Harvey, P. J.; Repine, J. T.; Sheehan, D. J.; VanderWel, S. N.; Zhou, H.; Keller, P. R.; McNamara, D. J.; Sherry, D.; Zhu, T.; Brodfuehrer, J.; Choi, C.; Barvian, M. R.; Fry, D. W. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6 J. Med. Chem. 2005, 48, 2388-2406
32. Saab, R.; Bills, J. L.; Miceli, A. P.; Anderson, C. M.; Khoury, J. D.; Fry, D. W.; Navid, F.; Houghton, P. J.; Skapek, S. X. Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells Mol. Cancer Ther. 2006, 5, 1299-1308
33. Baughn, L. B.; Di Liberto, M.; Wu, K.; Toogood, P. L.; Louie, T.; Gottschalk, R.; Niesvizky, R.; Cho, H.; Ely, S.; Moore, M. A.; Chen-Kiang, S. A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6 Cancer Res. 2006, 66, 7661-7667
34. Fry, D. W.; Bedford, D. C.; Harvey, P. H.; Fritsch, A.; Keller, P. R.; Wu, Z.; Dobrusin, E.; Leopold, W. R.; Fattaey, A.; Garrett, M. D. Cell cycle and biochemical effects of PD 0183812: a potent inhibitor of the cyclin D-dependent kinases CDK4 and CDK6 J. Biol. Chem. 2001, 276, 16617-16623
35. Marzec, M.; Kasprzycka, M.; Lai, R.; Gladden, A. B.; Wlodarski, P.; Tomczak, E.; Nowell, P.; Deprimo, S. E.; Sadis, S.; Eck, S.; Schuster, S. J.; Diehl, J. A.; Wasik, M. A. Mantle cell lymphoma cells express predominantly cyclin D1a isoform and are highly sensitive to selective inhibition of CDK4 kinase activity Blood 2006, 108, 1744-1750
36. Finn, R. S.; Dering, J.; Conklin, D.; Kalous, O.; Cohen, D. J.; Desai, A. J.; Ginther, C.; Atefi, M.; Chen, I.; Fowst, C.; Los, G.; Slamon, D. J. PD-0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro Breast Cancer Res. 2009, 11, R77
37. Michaud, K.; Solomon, D. A.; Oermann, E.; Kim, J. S.; Zhong, W. Z.; Prados, M. D.; Ozawa, T.; James, C. D.; Waldman, T. Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts Cancer Res. 2010, 70, 3228-3238
38. Wiedemeyer, W. R.; Dunn, I. F.; Quayle, S. N.; Zhang, J.; Chheda, M. G.; Dunn, G. P.; Zhuang, L.; Rosenbluh, J.; Chen, S.; Xiao, Y.; Shapiro, G. I.; Hahn, W. C.; Chin, L. Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM Proc. Natl. Acad. Sci.U. S. A. 2010, 107, 11501-11506
39. Konecny, G. E.; Winterhoff, B.; Kolarova, T.; Qi, J.; Manivong, K.; Dering, J.; Yang, G.; Chalukya, M.; Wang, H. J.; Anderson, L.; Kalli, K. R.; Finn, R. S.; Ginther, C.; Jones, S.; Velculescu, V. E.; Riehle, D.; Cliby, W. A.; Randolph, S.; Koehler, M.; Hartmann, L. C.; Slamon, D. J. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer Clin. Cancer Res. 2011, 17, 1591-1602
40. O'Dwyer, P. J.; LoRusso, P.; DeMichele, A.; Gupta, V.; Barbi, A.; Dial, H.; Chen, I.; Courtney, R.; wilner, K. D; Schwartz, G. K. A phase I dose escalation trial of a daily oral CDK 4/6 inhibitor PD-0332991 J. Clin. Oncol. 2007, 25 (18S) 150S (Suppl Abst-3550)
41. Schwartz, G. K.; LoRusso, P. M.; Dickson, M. A.; Randolph, S. S.; Shaik, M. N.; Wilner, K. D.; Courtney, R.; O'Dwyer, P. J. Phase I study of PD-0332991, a cyclin-dependent kinase inhibitor, administered in 3-week cycles (schedule 2/1) Br. J. Cancer 2011, 104, 1862-1868
42. Leonard, J. P.; LaCasce, A. S.; Smith, M. R.; Noy, A.; Chirieac, L. R.; Rodig, S. J.; Yu, J. Q.; Vallabhajosula, S.; Schoder, H.; English, P.; Neuberg, D. S.; Martin, P.; Millenson, M. M.; Ely, S. A.; Courtney, R.; Shaik, N.; Wilner, K. D.; Randolph, S.; Van den Abbeele, A.; Chen-Kiang, S. Y.; D. Yap, J. T.; Shapiro, G. I. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma Blood 2012, 119, 4597-4607
43. 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, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD0332991, administered using a 21-day schedule in patients with advanced cancer Clin. Cancer Res. 2012, 18, 568-576
44. Niesvizky, R.; Ely, S.; Jayabalan, D. S.; Manco, M.; Singhal, S.; Crann, M.; Courtney, R.; DuFresne, C.; Wilner, K.; Chen, I.; Mark, T.; Leonard, J. P.; Coleman, M.; DiLiberto, M.; Huang, X.; Chen-Kiang, S. A; Phase, I. Trial of PD-0332991, a Novel, Orally-Bioavailable CDK4/6-Specific Inhibitor Administered in Combination with Bortezomib and Dexamethasone to Patients with Relapsed and Refractory Multiple Myeloma. 51st American Society of Hematology Meeting, New Orleans, LA, December 5-8, 2009, Abst 1877.
45. Chen-Kiang, S.; Di Liberto, M.; Louie, T.; Liang, J.; Jayabalan, D. S.; Ely, S.; Moore, M. A.; Niesvizky, R.; Huang, X. Targeting Cdk4/6 in combination therapy of chemoresistant multiple myeloma. J. Clin. Oncol. 2008, 26, Abstract 8503.
46. Finn, R. S.; Crown, J. P.; Lang, I.; Boer, K.; Bondarenko, I. M.; Kulyk, S. O.; Ettl, J.; Patel, R.; Schmidt, M.; Shparyk, Y.; Thummala, A. R.; Voytko, N. L.; Breazna, A.; Kim, S. T.; Randolph, S.; Salmon, D. J. Results of randomized phase 2 study of PD 0332991, a cyclic-dependent kinase (CDK) 4/6 inhibitor, in combination with letrazole vs letrazole alone for first-line treatment of ER+/Her2- advanced breast cancer (BC). Cancer Res. 2012, 72, Suppl 24) Abstract no. S1-6.
47. Finn, R. S.; Veronique, D.; Karen, A.; Gelmon, N. H.; Stephen, E. J.; Maria, K.; Maguel, M.; Hope, S. R.; Seock-Aj, I.; Masakazu, T.; Eric, R. G.; Xin, H.; Sophia, R.; Dennis, J. S. A randomized, multicenter, double-blind phase III study of palbociclib (PD-0332991), an oral CDK 4/6 inhibitor, plus letrozole versus placebo plus letrazole for the treatment of postmenopausal women with ER(+), HER2(-) breast cancer who have not received any prior systemic anticancer treatment for advanced disease. J. Clin. Oncol. 2013, 31 (Suppl) Abstr TPS652.
48. Daren, R. V.; William, B.; Bayard, D. C.; Nikolas, V. B.; Justus, D. Pyridopyrimidine Kinase Inhibitors. U. S Patent 20050009849 A1, Jan 13, 2005.
49. Buhr, C. A.; Bajjalieh, W.; Joshi, A. B.; Lara, K.; Ma, S.; Marlowe, C. K.; Wang, L.; Yeung, B. N. S. Pyrido[2,3- d ]pyrimidin-7-one compounds as inhibitors of PI3K-ALPHA for the treatment of cancer. Canada Patent 2683784 A1, Oct 23, 2008.
50. Brian, D. P.; Jeff, B. S.; Gordon, W. R.; Ellen, M. D.; Alan, K.; Charles, W. M.; Randall, W. S.; William, A. D. Structure-activity relationships for 2-anilino-6-phenylpyrido[2,3- d ]pyrimidine-7(8 H)-ones a inhibitors of the cellular checkpoint kinase wee 1 Bioorg. Med. Chem. Lett. 2005, 15, 1931-1935
51. Reddy, M. V. R.; Mallireddigari, M. R.; Cosenza, S. C.; Pallela, V. R.; Iqbal, N. M.; Robell, K. A.; Kang, A. D.; Reddy, E. P. Design, Synthesis, and Biological Evaluation of (E)-Styrylbenzylsulfones as Novel Anticancer Agents J. Med. Chem. 2008, 51, 86-100
52. Reddy, M. V. R.; Reddy, S. Synthesis of α,β-Unsaturated Sulfones Acta Chim. Hung. 1984, 115, 269-271
53. Reddy, D. B.; Reddy, N. S.; Reddy, M. V. R.; Balasubramanyam, S. Preparation of Styryl Benzyl Sulfones and 1,2-Bis-(styrylsulfonylmethyl)-4,5- dimethylbenzenes Org. Prep. Proced. Int. 1988, 20, 205-212
54. Reddy, M. V. R.; Mallireddigari, M. R.; Pallela, V. R.; Venkatapuram, P.; Boominathan, R.; Bell, S. C.; Reddy, E. P. Design, synthesis, and biological evaluation of (E)-and (Z)-styryl-2-acetoxyphenyl sulfides and sulfones as cyclooxygenase-2 inhibitors Bioorg. Med. Chem. 2005, 13, 1715-1723
55. Reddy, N. S.; Gumireddy, K.; Mallireddigari, M. R.; Cosenza, S. C.; Venkatapuram, P.; Bell, S. C.; Reddy, E. P.; Reddy, M. V. R. Novel coumarin-3-(N -aryl)carboxamides arrest breast cancer cell growth by inhibiting ErbB-2 and ERK1 Bioorg. Med. Chem. 2005, 13, 3141-3147
56. Suzuki, A.; Lu, J.; Kusakai, G.; Kishimoto, A.; Ogura, T.; Esumi, H. ARK5 is a tumor invasion-associated factor downstream of Akt signaling Mol. Cell. Biol. 2004, 24, 3526-3535
57. Kusakai, G.; Suzuki, A.; Ogura, T.; Kaminishi, M.; Esumi, H. Strong association of ARK5 with tumor invasion and metastasis J. Exp. Clin. Cancer Res. 2004, 23, 263-268
58. Sutherland, R. L.; Musgrove, E. A. CDK inhibitors as potential breast cancer therapeutics: new evidence for enhanced efficacy in ER+ disease Breast Cancer Res. 2009, 11, 112
59. Kitagawa, M.; Higashi, H.; Jung, H. K.; Suzuki-Takahashi, I.; Ikeda, M.; Tamai, K.; Kato, J.; Segawa, K.; Yoshida, E.; Nishimura, S.; Taya, Y. The consensus motif for phosphorylation by cyclin D1-Cdk4 is different from that for phosphorylation by cyclin A/E-Cdk2 EMBO J. 1996, 15, 7060-7069
60. Connell-Crowley, L.; Harper, J. W.; Goodrich, D. W. Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation Mol. Biol. Cell 1997, 8, 287-301
61. Grafstrom, R. H.; Pan, W.; Hoess, R. H. Defining the substrate specificity of cdk4 kinase-cyclin D1 complex Carcinogenesis 1999, 202, 193-198
62. Hua, L. V.; Xiaoping, Z.; Jyoti, S.; Reddy, M. V. R.; Reddy, E. P.; James, M. G. Integrated pharmacokinetic-driven approach to screen candidate anticancer drugs for brain tumor chemotheraphy AAPS J. 2013, 15, 250-257