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

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Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL

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.

PubMed ID

15542782 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Palbociclib	Cyclin-dependent kinase 4	Protein	Humans	Yes	Inhibitor	Details
Palbociclib	Cyclin-dependent kinase 6	Protein	Humans	Yes	Inhibitor	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Palbociclib	Approved Investigational	CCNE2	9134	downregulated	palbociclib analog results in decreased expression of CCNE2 mRNA	8q22.1
Palbociclib	Approved Investigational	CDK1	983	downregulated	palbociclib analog results in decreased expression of CDK1 mRNA	10q21.2
Palbociclib	Approved Investigational	TK1	7083	downregulated	palbociclib analog results in decreased expression of TK1 mRNA	17q25.3
Palbociclib	Approved Investigational	TOP2A	7153	downregulated	palbociclib analog results in decreased expression of TOP2A mRNA	17q21.2