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

Molecular Cancer Therapeutics

Volumn 8, Issue 7, 2009, Pages 1856-1866

  Byth, Kate F ^a   Thomas, Andrew ^a   Hughes, Gareth ^a   Forder, Cheryl ^a   McGregor, Alexandra ^a   Geh, Catherine ^a   Oakes, Sandra ^a   Green, Clive ^a   Walker, Mike ^a   Newcombe, Nicholas ^a   Green, Stephen ^a   Growcott, Jim ^a   Barker, Andy ^a   Wilkinson, Robert W ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

AZD 5438; CYCLIN A; CYCLIN B1; CYCLIN D1; CYCLIN D3; CYCLIN DEPENDENT KINASE 1; CYCLIN DEPENDENT KINASE 2; CYCLIN DEPENDENT KINASE 9; CYCLIN DEPENDENT KINASE INHIBITOR; CYCLIN E; CYCLIN T1; FLAVOPIRIDOL; NUCLEOLIN; PHOSPHOPROTEIN PHOSPHATASE 1; RETINOBLASTOMA PROTEIN; RNA POLYMERASE II; ROSCOVITINE; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTINEOPLASTIC ACTIVITY; ARTICLE; CANCER CELL CULTURE; CANCER INHIBITION; CELL CYCLE ARREST; COLON CANCER; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG BLOOD LEVEL; DRUG POTENCY; DRUG TUMOR LEVEL; ENZYME INHIBITION; FEMALE; FLUORESCENCE ACTIVATED CELL SORTING; HUMAN; HUMAN CELL; IC 50; MOUSE; NONHUMAN; PHARMACODYNAMICS; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; TUMOR XENOGRAFT; WESTERN BLOTTING;

ANIMALS; ANTINEOPLASTIC AGENTS; BLOTTING, WESTERN; CDC2 PROTEIN KINASE; CELL CYCLE; CELL PROLIFERATION; CYCLIN-DEPENDENT KINASE 2; CYCLIN-DEPENDENT KINASE 9; CYCLIN-DEPENDENT KINASES; FEMALE; HUMANS; IMIDAZOLES; MICE; MICE, NUDE; NEOPLASMS; PYRIMIDINES; RATS; RATS, NUDE; TUMOR CELLS, CULTURED; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 67651177588     PISSN: 15357163     EISSN: None     Source Type: Journal    
DOI: 10.1158/1535-7163.MCT-08-0836     Document Type: Article

References (49)

1. Ortega S, Malumbres M, Barbacid M. Cyclin D-dependent kinases, INK4 inhibitors and cancer. Biochim Biophys Acta 2002;1:73-87.
2. Barton MC, Akli S, Keyomarsi K. Deregulation ofcycl in E meets dysfunction in p53: closing the escape hatch on breast cancer. J Cell Physiol 2006;209:686-94.
3. Lopez-Beltran A, MacLennan GT, Montironi R. Cyclin E as molecular marker in the management ofbreast cancer: a review. Anal Quant Cytol Histol 2006;28:111-14.
4. Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 2006;24:1770-783.
5. Malumbres M, Barbacid M. Mammalian cyclin-dependent kinases. Trends Biochem Sci 2005;30:630-41.
6. Santamaria D, Ortega S. Cyclins and CDKS in development and cancer: lessons from genetically modified mice. Front Biosci 2006;11:1164-88.
7. Aleem E, Kaldis P. Mouse models ofce ll cycle regulators: new paradigms. Results Probl Cell Differ 2006;42:271-328.
8. Aleem E, Kiyokawa H, Kaldis P. Cdc2-cyclin E complexes regulate the G1/S phase transition. Nat Cell Biol 2005;7:831-36.
9. Cai D, Latham VM, Jr., Zhang X, Shapiro GI. Combined depletion ofcell cycle and transcriptional cyclin-dependent kinase activities induces apoptosis in cancer cells. Cancer Res 2006;66:9270-80.
10. Fry DW, Harvey PJ, Keller PR, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004;3:1427-38.
11. Chen YN, Sharma SK, Ramsey TM, et al. Selective killing oftr ansformed cells by cyclin/cyclin-dependent kinase 2 antagonists. Proc Natl Acad Sci U S A 1999;96:4325-29.
12. Byth KF, Cooper N, Culshaw JD, et al. Imidazo[1,2-b]pyridazines: a potent and selective class ofcy clin-dependent kinase inhibitors. Bioorg Med Chem Lett 2004;14:2249-52.
13. Byth KF, Culshaw JD, Green S, Oakes SE, Thomas AP. Imidazo[1,2-a] pyridines. Part 2. SAR and optimisation ofa potent and selective class of cyclin-dependent kinase inhibitors. Bioorg Med Chem Lett 2004;14: 2245-48.
14. Byth KF, Geh C, Forder CL, Oakes SE, Thomas AP. The cellular phenotype of AZ703, a novel selective imidazo[1,2-a]pyridine cyclin-dependent kinase inhibitor. Mol Cancer Ther 2006;5:655-64.
15. Zaffaroni N, Pennati M, Daidone MG. Survivin as a target for new anticancer interventions. J Cell Mol Med 2005;9:360-72.
16. Goga A, Yang D, Tward AD, Morgan DO, Bishop JM. Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nat Med 2007;13:820-27.
17. Marshall RM, Grana X. Mechanisms controlling CDK9 activity. Front Biosci 2006;11:2598-613.
18. Peterlin BM, Price DH. Controlling the elongation phase oftranscription with P-TEFb. Mol Cell 2006;23:297-305.
19. Fisher RP. Secrets ofa double agent: CDK7 in cell-cycle control and transcription. J Cell Sci 2005;118:5171-180.
20. Cisek LJ, Corden JL. Phosphorylation of RNA polymerase by the murine homologue ofthe cell-cycle control protein cdc2. Nature 1989;339: 679-84.
21. Deng L, Ammosova T, Pumfery A, Kashanchi F, Nekhai S. HIV-1 Tat interaction with RNA polymerase II C-terminal domain (CTD) and a dynamic association with CDK2 induce CTD phosphorylation and transcription from HIV-1 promoter. J Biol Chem 2002;277:33922-929.
22. Byrd JC, Lin TS, Dalton JT, et al. Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 2007;109:399-404.
23. Camidge DR, Pemberton M, Growcott J, et al. A phase I pharmacodynamic study ofthe effects ofthe cyclin-dependent kinase-inhibitor AZD5438 on cell cycle markers within the buccal mucosa, plucked scalp hairs and peripheral blood mononucleocytes ofhea lthy male volunteers. Cancer Chemother Pharmacol 2007;60:479-88.
24. Anderson M, Andrews DM, Barker AJ, et al. Imidazoles: SAR and development ofa potent class of cyclin-dependent kinase inhibitors. Bioorg Med Chem Lett 2008;18:5487-92.
25. Dranovsky A, Vincent I, Gregori L, et al. Cdc2 phosphorylation ofnucleolin demarcates mitotic stages and Alzheimer's disease pathology. Neurobiol Aging 2001;22:517-28.
26. Wedge SR, Ogilvie DJ, Dukes M, et al. ZD4190: an orally active inhibitor ofva scular endothelial growth factor signaling with broad-spectrum antitumor efficacy. Cancer Res 2000;60:970-75.
27. Wilkinson RW, Odedra R, Heaton SP, et al. AZD1152, a selective inhibitor of Aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res 2007;13:3682-88.
28. McKillop D, Partridge EA, Kemp JV, et al. Tumor penetration ofgef itinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor. Mol Cancer Ther 2005;4:641-9.
29. Leclerc S, Garnier M, Hoessel R, et al. Indirubins inhibit glycogen synthase kinase-3β and CDK5/p25, two protein kinases involved in abnormal τ phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors? J Biol Chem 2001;276: 251-60.
30. Belenguer P, Caizergues-Ferrer M, Labbe JC, Doree M, Amalric F. Mitosis-specific phosphorylation of nucleolin by p34cdc2 protein kinase. Mol Cell Biol 1990;10:3607-18.
31. Dohadwala M, da Cruz e Silva EF, Hall FL, et al. Phosphorylation and inactivation ofpro tein phosphatase 1 by cyclin-dependent kinases. Proc Natl Acad Sci U S A 1994;91:6408-12.
32. Coverley D, Laman H, Laskey RA. Distinct roles for cyclins E and A during DNA replication complex assembly and activation. Nat Cell Biol 2002;4:523-28.
33. Harper JW, Adams PD. Cyclin-dependent kinases. Chem Rev 2001; 101:2511-26.
34. 1-phase progression. Genes Dev 1999;13:1501-12.
35. 2 phase roles for Cdk2 revealed by inducible expression ofa dominant-negative mutant in human cells. Mol Cell Biol 2001;21:2755-66.
36. Castedo M, Perfettini JL, Roumier T, Kroemer G. Cyclin-dependent kinase-1: linking apoptosis to cell cycle and mitotic catastrophe. Cell Death Differ 2002;9:1287-93.
37. Tetsu O, McCormick F. Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 2003;3:233-45.
38. Takaki T, Fukasawa K, Suzuki-Takahashi I, et al. Preferences for phosphorylation sites in the retinoblastoma protein of D-type cyclin-dependent kinases, Cdk4 and Cdk6, in vitro. J Biochem 2005;137:381-86.
39. 1/S cyclin-dependent kinases. J Biol Chem 1997; 272:12738-46.
40. Knudsen ES, Wang JYJ. Differential regulation of retinoblastoma protein function by specific Cdk phosphorylation sites. J Biol Chem 1996; 271:8313-20.
41. Connell-Crowley L, Harper JW, Goodrich DW. Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation. Mol Biol Cell 1997;8:287-301.
42. 795 is mediated by ERK1/2 in small intestine epithelial cells. J Biol Chem 2005;280: 35992-8.
43. Mishra S, Melino G, Murphy LJ. Transglutaminase 2 kinase activity facilitates protein kinase A-induced phosphorylation of retinoblastoma protein. J Biol Chem 2007;282:18108-15.
44. Hassler M, Singh S, Yue WW, et al. Crystal structure ofthe retinoblastoma protein N domain provides insight into tumor suppression, ligand interaction, and holoprotein architecture. Mol Cell 2007;28: 371-85.
45. Lents NH, Gorges LL, Baldassare JJ. Reverse mutational analysis reveals threonine-373 as a potentially sufficient phosphorylation site for inactivation ofthe retinoblastoma tumor suppressor protein (pRB). Cell Cycle 2006;5:1699-707.
46. Strock CJ, Park J-I, Nakakura EK, et al. Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential ofpros tate cancer cells. Cancer Res 2006;66:7509-15.
47. Goodyear S, Sharma MC. Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5. Exp Mol Pathol 2007;82:25-32.
48. Cai D, Byth KF, Shapiro GI. AZ703, an imidazo[1,2-a]pyridine inhibitor ofcyclin-dependent kinases 1 and 2, induces E2F-1-dependent apoptosis enhanced by depletion ofcy clin-dependent kinase 9. Cancer Res 2006; 66:435-44.
49. Camidge DR, Smethurst D, Growcott J, et al. A first-in-man phase I tolerability and pharmacokinetic study ofthe cyclin-dependent kinaseinhibitor AZD5438 in healthy male volunteers. Cancer Chemother Pharmacol 2007;60:391-98.