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A Novel Orally Active Small Molecule Potently Induces G₁ Arrest in Primary Myeloma Cells and Prevents Tumor Growth by Specific Inhibition of Cyclin-Dependent Kinase 4/6

Departments of ¹ Pathology and ² Medicine and ³ Graduate Program in Immunology and Microbial Pathogenesis, Weill Medical College of Cornell University; ⁴ Memorial Sloan-Kettering Cancer Center, New York, New York; and ⁵ Pfizer Global Research and Development, Ann Arbor, Michigan

Requests for reprints: Selina Chen-Kiang, Department of Pathology, Cornell University Medical College, 1300 York Avenue, C-338, New York, NY 10021. Phone: 212-746-6440; Fax: 212-746-7996; E-mail: sckiang{at}med.cornell.edu.

Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of cyclin-dependent kinase 4 (Cdk4)-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of bone marrow myeloma cells in vivo. Here, we show that by specific inhibition of Cdk4/6, the orally active small-molecule PD 0332991 potently induces G₁ arrest in primary bone marrow myeloma cells ex vivo and prevents tumor growth in disseminated human myeloma xenografts. PD 0332991 inhibits Cdk4/6 proportional to the cycling status of the cells independent of cellular transformation and acts in concert with the physiologic Cdk4/6 inhibitor p18^INK4c. Inhibition of Cdk4/6 by PD 0332991 is not accompanied by induction of apoptosis. However, when used in combination with a second agent, such as dexamethasone, PD 0332991 markedly enhances the killing of myeloma cells by dexamethasone. PD 0332991, therefore, represents the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in multiple myeloma and possibly other B-cell cancers. (Cancer Res 2006; 66(15): 7661-7)

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