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J. Biol. Chem., Vol. 276, Issue 20, 16617-16623, May 18, 2001
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From the Progression through the
G1 phase of the cell cycle requires phosphorylation
of the retinoblastoma gene product (pRb) by the cyclin
D-dependent kinases CDK4 and CDK6, whose activity can
specifically be blocked by the CDK inhibitor
p16INK4A. Misregulation of the pRb/cyclin
D/p16INK4A pathway is one of the most common events in
human cancer and has lead to the suggestion that inhibition of cyclin
D-dependent kinase activity may have therapeutic value as
an anticancer treatment. Through screening of a chemical library, we
initially identified the [2,3-d]pyridopyrimidines as inhibitors of
CDK4. Chemical modification resulted in the identification of PD
0183812 as a potent and highly selective inhibitor of both CDK4 and
CDK6 kinase activity, which is competitive with ATP. Flow cytometry
experiments showed that of the cell lines tested, only those expressing
pRb demonstrated a G1 arrest when treated with PD 0183812. This arrest correlated in terms of incubation time and potency with a
loss of pRb phosphorylation and a block in proliferation, which was
reversible. These results suggest a potential use of this
chemical class of compounds as therapeutic agents in the treatment of
tumors with functional pRb, possessing cell cycle aberrations in other
members of the pRb/cyclin D/p16INK4A pathway.
Cell Cycle and Biochemical Effects of PD 0183812
A POTENT INHIBITOR OF THE CYCLIN D-DEPENDENT KINASES CDK4 AND
CDK6*
,,
,,,,,, and**
Departments of Cancer Research and
Chemistry, Pfizer Global Research and Development, Ann Arbor
Laboratories, Ann Arbor, Michigan 48105, the
§ CRC Centre for Cancer Therapeutics at the Institute of Cancer
Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, United Kingdom,
¶ Cytokinetics, South San Francisco, California 94080, and
Onyx Pharmaceuticals, Richmond, California 94806
*
This study was supported by the UK Cancer Research Campaign
(CRC) and the Institute of Cancer Research, UK (to M. D. G.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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