Cell cycle and biochemical effects of PD 0183812. A potent inhibitor of the cyclin D-dependent kinases CDK4 and CDK6.
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 p16(INK4A). Misregulation of the pRb/cyclin D/p16(INK4A) 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/p16(INK4A) pathway.
Fry
D W
DW
Department of Cancer Research, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, Michigan 48105, USA.
Bedford
D C
DC
Harvey
P H
PH
Fritsch
A
A
Keller
P R
PR
Wu
Z
Z
Dobrusin
E
E
Leopold
W R
WR
Fattaey
A
A
Garrett
M D
MD
D000818:Animals; D001943:Breast Neoplasms; D002453:Cell Cycle / Q000187:drug effects*; D002460:Cell Line; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins; D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D018411:Spodoptera; D014162:Transfection; D014407:Tumor Cells, Cultured
D056741:Cyclin D; D016213:Cyclins; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; C429523:PD 0183812; D011518:Proto-Oncogene Proteins; D011728:Pyridones; D011743:Pyrimidines; D011994:Recombinant Proteins; D016160:Retinoblastoma Protein; D017346:Protein Serine-Threonine Kinases; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases