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.