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AstraZeneca, Alderley Park, Macclesfield, United Kingdom

Requests for reprints: Kate F. Byth, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451. Phone: 781-839-4144; Fax: 781-839-4200. E-mail: Kate.Byth{at}astrazeneca.com

Because the majority of cancers exhibit direct or indirect deregulation of cyclin-dependent kinase (CDK) function, members of the CDK family are attractive targets for the development of anticancer agents. As part of an ongoing program, novel imidazopyridines were identified and developed as potent and selective CDK inhibitors. Here, we describe data on the in vitro biological activities of one of these compounds, AZ703. The selectivity profile of AZ703 was investigated in kinase assays against a range of CDK enzymes as well as a panel of protein kinases in vitro. IC₅₀s were assessed against different tumor cell lines in vitro. The mechanism of action of AZ703 was determined by observing changes in phosphorylation of CDK substrates and cell cycle effects on tumor and normal cells. In vitro studies revealed that AZ703 is a selective inhibitor of CDK1 and CDK2 and displays a mode of action consistent with the induction of G₁-, S-, and G₂-M-phase arrest. AZ703 also showed potent antiproliferative activity across a wide range of tumor cell lines in vitro. Moreover, AZ703 induced reversible blockade of normal cells while causing tumor cells to undergo apoptosis. We have identified AZ703 as a novel selective imidazo[1,2-a]pyridine CDK inhibitor that shows promising antitumor properties in vitro. [Mol Cancer Ther 2006;5(3):655–64]

Received 6/20/05; revised 12/11/05; accepted 1/10/06.