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

David W Fry; Patricia J Harvey; Paul R Keller; William L Elliott; Maryanne Meade; Erin Trachet; Mudher Albassam; XianXian Zheng; Wilbur R Leopold; Nancy K Pryer; Peter L Toogood

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

Mol Cancer Ther. 2004 Nov;3(11):1427-38.

Authors

David W Fry¹, Patricia J Harvey, Paul R Keller, William L Elliott, Maryanne Meade, Erin Trachet, Mudher Albassam, XianXian Zheng, Wilbur R Leopold, Nancy K Pryer, Peter L Toogood

Affiliation

¹ Cancer Pharmacology, Pfizer Global Research and Development, Ann Arbor, Michigan 48105, USA.

PMID: 15542782

Abstract

PD 0332991 is a highly specific inhibitor of cyclin-dependent kinase 4 (Cdk4) (IC50, 0.011 micromol/L) and Cdk6 (IC50, 0.016 micromol/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.

MeSH terms

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*

Substances

Antineoplastic Agents
Piperazines
Protein Kinase Inhibitors
Proto-Oncogene Proteins
Pyridines
Retinoblastoma Protein
CDK4 protein, human
CDK6 protein, human
Cdk4 protein, mouse
Cdk6 protein, mouse
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Cyclin-Dependent Kinases
palbociclib