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

• Published in: Molecular cancer therapeutics Vol. 3; no. 11; pp. 1427 - 1438
• Main Authors: Fry, David W, Harvey, Patricia J, Keller, Paul R, Elliott, William L, Meade, Maryanne, Trachet, Erin, Albassam, Mudher, Zheng, XianXian, Leopold, Wilbur R, Pryer, Nancy K, Toogood, Peter L
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01-11-2004
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinases - antagonists & inhibitors; Cyclin-Dependent Kinases - metabolism; Disease Models, Animal; Down-Regulation - drug effects; G1 Phase - drug effects; Humans; Mice; Molecular Structure; Neoplasm Transplantation - pathology; Neoplasms - metabolism; Neoplasms - pathology; Phosphorylation - drug effects; Piperazines - chemistry; Piperazines - pharmacology; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - metabolism; Pyridines - chemistry; Pyridines - pharmacology; Retinoblastoma Protein - metabolism; Substrate Specificity; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.1427.3.11

PD 0332991 is a highly specific inhibitor of cyclin-dependent kinase 4 (Cdk4) (IC 50 , 0.011 μmol/L) and Cdk6 (IC 50 , 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 G 1 arrest, with a concomitant reduction of phospho-Ser 780 /Ser 795 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.