This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cai, D. Articles by Shapiro, G. I. Search for Related Content PubMed PubMed Citation Articles by Cai, D. Articles by Shapiro, G. I.

AZ703, an Imidazo[1,2-a]Pyridine Inhibitor of Cyclin-Dependent Kinases 1 and 2, Induces E2F-1-Dependent Apoptosis Enhanced by Depletion of Cyclin-Dependent Kinase 9

¹ Department of Medical Oncology, Dana-Farber Cancer Institute; ² Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and ³ AstraZeneca, Alderley Park, Cheshire, United Kingdom

Requests for reprints: Geoffrey I. Shapiro, Dana-Farber Cancer Institute, Dana 810A, 44 Binney Street, Boston, MA 02115. Phone: 617-632-4942; Fax: 617-632-1977; E-mail: geoffrey_shapiro{at}dfci.harvard.edu.

Preclinical studies were performed of a novel selective imidazopyridine cyclin-dependent kinase (cdk) inhibitor, AZ703. In vitro kinase assays showed that IC₅₀ values for AZ703 against purified cyclin E/cdk2 and cyclin B/cdk1 were 34 and 29 nmol/L, respectively. In contrast, the IC₅₀ against cdk4 was >10 µmol/L. AZ703 also inhibited cdk7 and cdk9 with IC₅₀ values of 2.1 µmol/L and 521 nmol/L, respectively. Treatment of U2OS, NCI-H1299, and A549 cells for 24 hours resulted in growth arrest involving multiple cell cycle phases. At low drug concentrations (<2 µmol/L), G₂ arrest predominated, whereas at higher concentrations (2 µmol/L), S-G₂ arrest was observed. When cells were synchronized in G₁ by starvation and released into AZ703, a block in G₁ occurred that was not evident in exponentially growing cells. Cell cycle arrest was associated with reduced phosphorylation of the retinoblastoma protein and p27^Kip1 at cdk2 phospho-sites. Following longer exposures, apoptosis was evident. Cells were further sensitized to AZ703 following recruitment to S phase by synchronization. Consistent with the inhibition of cdks during S and G₂ that modulate the activity and stability of E2F-1, AZ703 treatment induced E2F-1 expression. In U2OS and NCI-H1299 cells engineered to inducibly express the dominant-negative mutant E2F-1 (1-374), expression of the mutant decreased AZ703-mediated apoptosis, indicating dependence on E2F-1 transcriptional targets. AZ703-induced apoptosis in NCI-H1299 cells was enhanced by small interfering RNA–mediated depletion of cdk9, which caused reduced levels of Mcl-1 and XIAP, suggesting that cdk2, cdk1, and cdk9 represent a rational subset of family members for drug targeting. (Cancer Res 2006; 66(1): 435-44)

This article has been cited by other articles:

				D. S. Boss, G. K. Schwartz, M. R. Middleton, D. D. Amakye, H. Swaisland, R. S. Midgley, M. Ranson, S. Danson, H. Calvert, R. Plummer, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours Ann. Onc., October 13, 2009; (2009) mdp377v1. [Abstract] [Full Text] [PDF]

				K. F. Byth, A. Thomas, G. Hughes, C. Forder, A. McGregor, C. Geh, S. Oakes, C. Green, M. Walker, N. Newcombe, et al. 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., July 1, 2009; 8(7): 1856 - 1866. [Abstract] [Full Text] [PDF]

				T. Eguchi, H. Itadani, T. Shimomura, N. Kawanishi, H. Hirai, and H. Kotani Expression levels of p18INK4C modify the cellular efficacy of cyclin-dependent kinase inhibitors via regulation of Mcl-1 expression in tumor cell lines Mol. Cancer Ther., June 1, 2009; 8(6): 1460 - 1472. [Abstract] [Full Text] [PDF]

				A Scholz, K Wagner, M Welzel, F Remlinger, B Wiedenmann, G Siemeister, S Rosewicz, and K M Detjen The oral multitarget tumour growth inhibitor, ZK 304709, inhibits growth of pancreatic neuroendocrine tumours in an orthotopic mouse model Gut, February 1, 2009; 58(2): 261 - 270. [Abstract] [Full Text] [PDF]

				K. Bettayeb, O. M. Tirado, S. Marionneau-Lambot, Y. Ferandin, O. Lozach, J. C. Morris, S. Mateo-Lozano, P. Drueckes, C. Schachtele, M. H.G. Kubbutat, et al. Meriolins, a New Class of Cell Death Inducing Kinase Inhibitors with Enhanced Selectivity for Cyclin-Dependent Kinases Cancer Res., September 1, 2007; 67(17): 8325 - 8334. [Abstract] [Full Text] [PDF]

				W. DePinto, X.-J. Chu, X. Yin, M. Smith, K. Packman, P. Goelzer, A. Lovey, Y. Chen, H. Qian, R. Hamid, et al. 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., November 1, 2006; 5(11): 2644 - 2658. [Abstract] [Full Text] [PDF]

				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., September 15, 2006; 66(18): 9270 - 9280. [Abstract] [Full Text] [PDF]

				G. I. Shapiro Cyclin-Dependent Kinase Pathways As Targets for Cancer Treatment J. Clin. Oncol., April 10, 2006; 24(11): 1770 - 1783. [Abstract] [Full Text] [PDF]

				K. F. Byth, C. Geh, C. L. Forder, S. E. Oakes, and A. P. Thomas The cellular phenotype of AZ703, a novel selective imidazo[1,2-a]pyridine cyclin-dependent kinase inhibitor. Mol. Cancer Ther., March 1, 2006; 5(3): 655 - 664. [Abstract] [Full Text] [PDF]