lin-Dependent Kinase Inhibitor

ownload lin-dependent kinases (CDK) are key positive regulators of cell cycle progression and attractive targets ology. SCH 727965 inhibits CDK2, CDK5, CDK1, and CDK9 activity in vitro with IC50 values of 1, 1, 3, nmol/L, respectively. SCH 727965 was selected as a clinical candidate using a functional screen in vivo tegrated both efficacy and safety parameters. Comparedwith flavopiridol, SCH 727965 exhibits superior y with an improved therapeutic index. In cell-based assays, SCH 727965 completely suppressed retinoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine oration in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH were sufficient for long-lasting cellular effects. SCH 727965 induced regression of established solid tun a range of mouse models following intermittent scheduling of doses below the maximally tolerated This was associated with modulation of pharmacodynamic biomarkers in skin punch biopsies and rapidly reversible, mechanism-based effects on hematologic parameters. These results suggest that SCH 727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent. Mol Cancer Ther; 9(8); 2344–53. ©2010 AACR.