Synthesis, structure-activity relationship and biological evaluation of 2,4,5-trisubstituted pyrimidine CDK inhibitors as potential anti-tumour agents

European Journal of Medicinal Chemistry

Volumn 70, Issue , 2013, Pages 447-455

  Shao, Hao ^a   Shi, Shenhua ^a   Foley, David W ^a   Lam, Frankie ^a,b   Abbas, Abdullah Y ^a   Liu, Xiangrui ^a   Huang, Shiliang ^a   Jiang, Xiangrui ^a   Baharin, Nadiah ^a   Fischer, Peter M ^a   Wang, Shudong ^a,b  

^a UNIVERSITY OF NOTTINGHAM   (United Kingdom)

^b UNIVERSITY OF SOUTH AUSTRALIA   (Australia)

Author keywords

Anti cancer drug discovery; CDK9 inhibitors; Inhibitor design; Mcl 1 anti apoptotic proteins; RNA polymerase II

Indexed keywords

(3 ((4 (4 METHYL 2 (METHYLAMINO)THIAZOL 5 YL)PYRIMIDIN 2 YL)AMINO)PHENYL) (MORPHOLINO)METHANONE; 1 (4 (3 (4 (2 AMINO 4 METHYLTHIAZOL 5 YL) 5 FLUOROPYRIMIDIN 2 YLAMINO)PHENYL) PIPERAZIN 1 YL)ETHANONE; 2 ((2 CHLORO 5 (4 METHYLPIPERAZINE 1 CARBONYL)PHENYL) AMINO) 4 (4 METHYL 2 (METHYLAMINO)THIAZOL 5 YL)PYRIMIDINE 5 CARBONITRILE; 2 ((3 (4 ACETYLPIPERAZINE 1 CARBONYL)PHENYL)AMINO) 4 (4 METHYL 2 (METHYLAMINO)THIAZOL 5 YL)PYRIMIDINE 5 CARBONITRILE; 3 ((4 (2 AMINO 4 METHYLTHIAZOL 5 YL) 5 FLUOROPYRIMIDIN 2 YL)AMINO)BENZENESULFONAMIDE; 3 ((5 CYANO 4 (4 METHYL 2 (METHYLAMINO)THIAZOL 5 YL) PYRIMIDIN 2 YL)AMINO) N (2 METHOXYETHYL)BENZENESULFONAMIDE; 3 (5 CYANO 4 (4 METHYL 2 (METHYLAMINO)THIAZOL 5 YL) PYRIMIDIN 2 YLAMINO) N (1 METHYLPIPERIDIN 4 YL)BENZAMIDE; 3 (5 FLUORO 4 (4 METHYL 2 (METHYLAMINO)THIAZOL 5 YL) PYRIMIDIN 2 YLAMINO) N (1 METHYLPIPERIDIN 4 YL)BENZAMIDE; 3 (5 FLUORO 4 (4 METHYL 2 (METHYLAMINO)THIAZOL 5 YL) PYRIMIDIN 2 YLAMINO) N (2 METHOXYETHYL)BENZENESULFONAMIDE; 4 (4 METHYL 2 (METHYLAMINO)THIAZOL 5 YL) 2 ((3 ((4 METHYLPIPERAZIN 1 YL)SULFONYL)PHENYL)AMINO)PYRIMIDINE 5 CARBONITRILE; 4 (4 METHYL 2 (METHYLAMINO)THIAZOL 5 YL) 2 ((3 (4 METHYLPIPERAZINE 1 CARBONYL)PHENYL)AMINO)PYRIMIDINE 5 CARBONITRILE; 4 (4 METHYL 2 (METHYLAMINO)THIAZOL 5 YL) 2 ((3 (METHYLSULFONYL)PHENYL)AMINO) PYRIMIDINE 5 CARBONITRILE; 4 (4 METHYL 2 (METHYLAMINO)THIAZOL 5 YL) 2 ((3 (MORPHOLINOSULFONYL)PHENYL)AMINO)PYRIMIDINE 5 CARBONITRILE; 4 (5 CYANO 4 (4 METHYL 2 (METHYLAMINO)THIAZOL 5 YL) PYRIMIDIN 2 YLAMINO) N (1 METHYLPIPERIDIN 4 YL)BENZAMIDE; 5 (5 FLUORO 2 (3 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO) PYRIMIDIN 4 YL) 4 METHYLTHIAZOL 2 AMINE; 5 (5 FLUORO 2 (3 (4 METHYLPIPERAZIN 1 YL)PHENYLAMINO) PYRIMIDIN 4 YL) N,4 DIMETHYLTHIAZOL 2 AMINE; 5 (5 FLUORO 2 (4 METHYL 3 (MORPHOLINOSULFONYL) PHENYLAMINO)PYRIMIDIN 4 YL) N,4 DIMETHYLTHIAZOL 2 AMINE; ANTINEOPLASTIC AGENT; CASPASE 3; CYCLIN DEPENDENT KINASE 9; CYCLIN DEPENDENT KINASE INHIBITOR; PROTEIN MCL 1; PYRIMIDINE DERIVATIVE; UNCLASSIFIED DRUG;

ANTIPROLIFERATIVE ACTIVITY; APOPTOSIS; ARTICLE; BREAST CARCINOMA; CANCER CELL; COLON CARCINOMA; COLORECTAL CARCINOMA; CONTROLLED STUDY; DRUG CYTOTOXICITY; DRUG SYNTHESIS; ENZYME ACTIVATION; FEMALE; HUMAN; HUMAN CELL; LUNG CARCINOMA; OVARY CARCINOMA; PANCREAS CARCINOMA; STRUCTURE ACTIVITY RELATION; UTERINE CERVIX CARCINOMA;

ANTI-CANCER DRUG DISCOVERY; CDK9 INHIBITORS; INHIBITOR DESIGN; MCL-1 ANTI-APOPTOTIC PROTEINS; RNA POLYMERASE II;

ANTINEOPLASTIC AGENTS; CELL PROLIFERATION; CYCLIN-DEPENDENT KINASES; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG SCREENING ASSAYS, ANTITUMOR; HCT116 CELLS; HUMANS; MCF-7 CELLS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84886735484     PISSN: 02235234     EISSN: 17683254     Source Type: Journal    
DOI: 10.1016/j.ejmech.2013.08.052     Document Type: Article

References (27)

1. S. Lapenna, and A. Giordano Cell cycle kinases as therapeutic targets for cancer Nat. Rev. Drug Discov. 8 2009 547 566
2. G.I. Shapiro Cyclin-dependent kinase pathways as targets for cancer treatment J. Clin. Oncol. 24 2006 1770 1783 (Pubitemid 46628473)
3. M. Malumbres, R. Sotillo, D. Santamaria, J. Galan, A. Cerezo, S. Ortega, P. Dubus, and M. Barbacid Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6 Cell 118 2004 493 504 (Pubitemid 39485668)
4. D. Cai, V.M. Latham Jr., X. Zhang, and G.I. Shapiro Combined depletion of cell cycle and transcriptional cyclin-dependent kinase activities induces apoptosis in cancer cells Cancer Res. 66 2006 9270 9280 (Pubitemid 44521149)
5. C. Berthet, E. Aleem, V. Coppola, L. Tessarollo, and P. Kaldis Cdk2 knockout mice are viable Curr. Biol. 13 2003 1775 1785 (Pubitemid 37274109)
6. C. Barriere, D. Santamaria, A. Cerqueira, J. Galan, A. Martin, S. Ortega, M. Malumbres, P. Dubus, and M. Barbacid Mice thrive without Cdk4 and Cdk2 Mol. Oncol. 1 2007 72 83 (Pubitemid 46776620)
7. D. Santamaria, C. Barriere, A. Cerqueira, S. Hunt, C. Tardy, K. Newton, J.F. Caceres, P. Dubus, M. Malumbres, and M. Barbacid Cdk1 is sufficient to drive the mammalian cell cycle Nature 448 2007 811 U818
8. M. Guha Blockbuster dreams for Pfizer's CDK inhibitor Nat. Biotechnol. 31 2013 187-187
9. M. Malumbres, P. Pevarello, M. Barbacid, and J.R. Bischoff CDK inhibitors in cancer therapy: what is next? Trends Pharmacol. Sci. 29 2008 16 21
10. R.P. Fisher Secrets of a double agent: CDK7 in cell-cycle control and transcription J. Cell Sci. 118 2005 5171 5180 (Pubitemid 41819581)
11. R. Shiekhattar, F. Mermelstein, R.P. Fisher, R. Drapkin, B. Dynlacht, H.C. Wessling, D.O. Morgan, and D. Reinberg Cdk-activating kinase complex is a component of human transcription factor TFIIH Nature 374 1995 283 287
12. D.H. Price P-TEFb, a cyclin-dependent kinase controlling elongation by RNA polymerase II Mol. Cell. Biol. 20 2000 2629 2634 (Pubitemid 30183481)
13. R.M. Marshall, and X. Grana Mechanisms controlling CDK9 activity Front. Biosci. 11 2006 2598 2613 (Pubitemid 43806567)
14. S. Wang, and P.M. Fischer Cyclin-dependent kinase 9: a key transcriptional regulator and potential drug target in oncology, virology and cardiology Trends Pharmacol. Sci. 29 2008 302 313
15. R. Chen, M.J. Keating, V. Gandhi, and W. Plunkett Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death Blood 106 2005 2513 2519 (Pubitemid 41510827)
16. L. Meijer, and E. Raymond Roscovitine and other purines as kinase inhibitors. From starfish oocytes to clinical trials Acc. Chem. Res. 36 2003 417 425
17. S.J. McClue, D. Blake, R. Clarke, A. Cowan, L. Cummings, P.M. Fischer, M. MacKenzie, J. Melville, K. Stewart, S. Wang, N. Zhelev, D. Zheleva, and D.P. Lane In vitro and in vivo antitumor properties of the cyclin dependent kinase inhibitor CYC202 (R-roscovitine) Int. J. Cancer. 102 2002 463 468 (Pubitemid 35315999)
18. K. Bettayeb, D. Baunbaek, C. Delehouze, N. Loaec, A.J. Hole, S. Baumli, J.A. Endicott, S. Douc-Rasy, J. Benard, N. Oumata, H. Galons, and L. Meijer CDK inhibitors roscovitine and CR8 trigger Mcl-1 down-regulation and apoptotic cell death in neuroblastoma cells Genes & Cancer 1 2010 369 380
19. M. Guha Cyclin-dependent kinase inhibitors move into phase III Nat. Rev. Drug Discov. 11 2012 892 894
20. H. Shao, S. Shi, S. Huang, A.J. Hole, A.Y. Abbas, S. Baumli, X. Liu, F. Lam, D.W. Foley, P.M. Fischer, M. Noble, J.A. Endicott, C. Pepper, and S. Wang Substituted 4-(thiazol-5-yl)-2-(phenylamino)pyrimidines are highly active CDK9 inhibitors: synthesis, X-ray crystal structures, structure-activity relationship, and anticancer activities J. Med. Chem. 56 2013 640 659
21. P.M. Lukasik, S. Elabar, F. Lam, H. Shao, X. Liu, A.Y. Abbas, and S. Wang Synthesis and biological evaluation of imidazo[4,5-b]pyridine and 4-heteroaryl-pyrimidine derivatives as anti-cancer agents Eur. J. Med. Chem. 57 2012 311 322
22. H.M. Alkahtani, A.Y. Abbas, and S. Wang Synthesis and biological evaluation of benzo[d]imidazole derivatives as potential anti-cancer agents Bioorg. Med. Chem. Lett. 22 2012 1317 1321
23. S.D. Wang, G. Griffiths, C.A. Midgley, A.L. Barnett, M. Cooper, J. Grabarek, L. Ingram, W. Jackson, G. Kontopidis, S.J. McClue, C. McInnes, J. McLachlan, C. Meades, M. Mezna, I. Stuart, M.P. Thomas, D.I. Zheleva, D.P. Lane, R.C. Jackson, D.M. Glover, D.G. Blake, and P.M. Fischer Discovery and characterization of 2-anilino-4-(thiazol-5-yl)pyrimidine transcriptional CDK inhibitors as anticancer agents Chem. Biol. 17 2010 1111 1121
24. S.D. Wang, C. Meades, G. Wood, A. Osnowski, S. Anderson, R. Yuill, M. Thomas, M. Mezna, W. Jackson, C. Midgley, G. Griffiths, I. Fleming, S. Green, I. McNae, S.Y. Wu, C. McInnes, D. Zheleva, M.D. Walkinshaw, and P.M. Fischer 2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity J. Med. Chem. 47 2004 1662 1675 (Pubitemid 38380910)
25. A.J. Hole, S. Baumli, H. Shao, S. Shi, S. Huang, C. Pepper, P.M. Fischer, S. Wang, J.A. Endicott, and M.E. Noble Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity J. Med. Chem. 56 2013 660 670
26. G. Nemeth, Z. Varga, Z. Greff, G. Bencze, A. Sipos, C. Szantai-Kis, F. Baska, A. Gyuris, K. Kelemenics, Z. Szathmary, J. Minarovits, G. Keri, and L. Orfi Novel, selective CDK9 inhibitors for the treatment of HIV infection Curr. Med. Chem. 18 2011 342 358
27. X. Liu, S. Shi, F. Lam, C. Pepper, P.M. Fischer, and S. Wang CDKI-71, a novel CDK9 inhibitor, is preferentially cytotoxic to cancer cells compared to flavopiridol Int. J. Cancer. Journal International du Cancer 130 2012 1216 1226