Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts

DW Fry, PJ Harvey, PR Keller, WL Elliott… - Molecular cancer …, 2004 - AACR
DW Fry, PJ Harvey, PR Keller, WL Elliott, MA Meade, E Trachet, M Albassam, XX Zheng…
Molecular cancer therapeutics, 2004AACR
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 …
Abstract
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.
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