Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts.
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.
Fry
David W
DW
Cancer Pharmacology, Pfizer Global Research and Development, Ann Arbor, Michigan 48105, USA.
Harvey
Patricia J
PJ
Keller
Paul R
PR
Elliott
William L
WL
Meade
Maryanne
M
Trachet
Erin
E
Albassam
Mudher
M
Zheng
XianXian
X
Leopold
Wilbur R
WR
Pryer
Nancy K
NK
Toogood
Peter L
PL
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D009368:Neoplasm Transplantation / Q000473:pathology; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D013379:Substrate Specificity; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011725:Pyridines; D016160:Retinoblastoma Protein; C495900:CDK4 protein, human; C495911:CDK6 protein, human; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; C500026:palbociclib