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Research Articles: Therapeutics, Targets, and Development

Pharmacologic properties of AG-012986, a pan-cyclin-dependent kinase inhibitor with antitumor efficacy

Departments of ¹ Cancer Biology, ² Pharmacokinetics, Dynamics and Metabolism, ³ Drug Safety Research and Development, ⁴ Biochemical Pharmacology, and ⁵ Medicinal Chemistry, Pfizer Global Research and Development, La Jolla, California

Requests for reprints: Cathy Zhang, Department of Cancer Biology, Pfizer Global Research and Development, 10724 Science Center Road, San Diego, CA 92121. Phone: 858-622-3125. E-mail: cathy.zhang{at}pfizer.com

Abstract

AG-012986 is a multitargeted cyclin-dependent kinase (CDK) inhibitor active against CDK1, CDK2, CDK4/6, CDK5, and CDK9, with selectivity over a diverse panel of non-CDK kinases. Here, we report the potent antitumor efficacies of AG-012986 against multiple tumor lines in vitro and in vivo. AG-012986 showed antiproliferative activities in vitro with IC₅₀s of <100 nmol/L in 14 of 18 tumor cell lines. In vivo, significant antitumor efficacy induced by AG-012986 was seen (tumor growth inhibition, >83.1%) in 10 of 11 human xenograft tumor models when administered at or near the maximum tolerated dose for 8 or 12 days. AG-012986 caused dose-dependent hypophosphorylation at Ser⁷⁹⁵ of the retinoblastoma protein, cell cycle arrest, and apoptosis in vitro. Colony-forming assays indicated that the potency of AG-012986 substantially decreased with treatment time of <24 h. In vivo, AG-012986 also showed dose-dependent retinoblastoma Ser⁷⁹⁵ hypophosphorylation, cell cycle arrest, decreased Ki-67 tumor staining, and apoptosis in conjunction with antitumor activity. Studies comparing i.p. bolus with s.c. implanted minipump dosing regimens revealed that in vivo efficacy correlated with the duration of minimally effective plasma levels rather than maximal drug plasma levels. Dosing optimization of AG-012986 provided guidance for selecting a treatment schedule to achieve the best antitumor efficacy while minimizing the risk of adverse side effects. [Mol Cancer Ther 2008;7(4):818–28]

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Note: All authors are present or former employees of Pfizer. The current address of former Pfizer employees is available upon request.

⁶ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 6/28/07; revised 12/ 6/07; accepted 2/ 8/08.