Cyclin-dependent kinase modulators studied at the NCI: pre-clinical and clinical studies

The cyclin dependent kinases (CDKs) are key regulators of cell cycle progression. Lead compounds (from empirical anti-proliferative screening approaches) have been defined which modulate CDK function and have evidence of anti-proliferative activity in tissue culture systems and in some cases anti-tumor activity in vivo in conventional xenogaft models. Two of these, flavopiridol and UCN-01, have entered initial clinical testing. Flavopiridol is a "pan-CDK" inhibitor, with essentially equal potency in inhibiting all CDKs tested. The recent elucidation that in addition to cell cycle regulatory functions, CDK family members have been defined which regulate transcription, neuronal, and secretory function has increased the need for definition of CDK antagonists with greater selectivity. Novel purine, pyrimidine, and benzazepinone derivatives have been characterized in part through the National Cancer Institute's drug screening systems. UCN-01, in contrast to flavopiridol, modulates CDK activity participating in the DNA damage response, possibly through potent inhibition of the chk1 checkpoint kinase, as well as affecting CDK function indirectly through activity on other kinase targets. An unexpected feature in its development has been avid binding to alpha(1) acid glycoprotein. Further progress in CDK modulator development will require the definition of additional lead structures that address issues raised by these early molecules entering into clinical development.