Cell cycle and biochemical effects of PD 0183812 - a potent inhibitor of the cyclin D-dependent kinases CDK4 and CDK6

Progression through the G(1) phase of the cell cycle requires phosphorylati on of the retinoblastoma gene product (pRb) by the cyclin D-dependent kinas es CDK4 and CDK6, whose activity can specifically be blocked by the CDK inh ibitor 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 suggestio n that inhibition of cyclin D-dependent kinase activity may have therapeuti c value as an anticancer treatment. Through screening of a chemical library , we initially identified the [2,3-d]pyridopyrimidines as inhibitors of CDK 4, Chemical modification resulted in the identification of PD 0183812 as a potent and highly se!lective inhibitor of both CDK4 and CDK6 kinase activit y, which is competitive with ATP, Flow cytometry experiments showed that of the cell lines tested, only those expressing pRb demonstrated a G(1) arres t when treated with PD 0183812, This arrest correlated in terms of incubati on time and potency with a loss of pRb phosphorylation and a block in proli feration, which was reversible, These results suggest a potential use of th is chemical class of compounds as therapeutic agents in the treatment of tu mors with functional pRb, possessing cell cycle aberrations in other member s of the pRb/cyclin D/p16(INK4A) pathway.