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¹ Cancer Pharmacology, ² Worldwide Safety Sciences, ³ Molecular Technologies, and ⁴ Medicinal Chemistry, Pfizer Global Research and Development, Ann Arbor, Michigan and ⁵ Onyx Pharmaceuticals, Richmond, California

Requests for reprints: Peter L. Toogood, Medicinal Chemistry, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, MI 48105. Phone: 734-622-1335; Fax: 734-622-5165. E-mail: Peter.Toogood2{at}Pfizer.com

PD 0332991 is a highly specific inhibitor of cyclin-dependent kinase 4 (Cdk4) (IC₅₀, 0.011 µmol/L) and Cdk6 (IC₅₀, 0.016 µmol/L), having no activity against a panel of 36 additional protein kinases. It is a potent antiproliferative agent against retinoblastoma (Rb)-positive tumor cells in vitro, inducing an exclusive G₁ arrest, with a concomitant reduction of phospho-Ser⁷⁸⁰/Ser⁷⁹⁵ on the Rb protein. Oral administration of PD 0332991 to mice bearing the Colo-205 human colon carcinoma produces marked tumor regression. Therapeutic doses of PD 0332991 cause elimination of phospho-Rb and the proliferative marker Ki-67 in tumor tissue and down-regulation of genes under the transcriptional control of E2F. The results indicate that inhibition of Cdk4/6 alone is sufficient to cause tumor regression and a net reduction in tumor burden in some tumors.

⁶ The discovery and preparation of PD 0332991 is described separately. PL Toogood, PJ Harvey, JT Refine, et al. Discovery of PD 0332991, a potent and selective Cdk 4/6 inhibitor, submitted for publication.

Received 5/ 5/04; revised 8/25/04; accepted 8/31/04.