Publication details
Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor
| Authors | |
|---|---|
| Year of publication | 2010 |
| Type | Article in Periodical |
| Magazine / Source | Molecular Cancer Therapeutics |
| MU Faculty or unit | |
| Citation | |
| Field | Oncology and hematology |
| Keywords | kinase; cdk; inhibitor; cancer |
| Description | yclin-dependent kinases (CDK) are key pos. regulators of cell cycle progression and attractive targets in oncol. SCH 727965 inhibits CDK2, CDK5, CDK1, and CDK9 activity in vitro with IC50 values of 1, 1, 3, and 4 nmol/L, resp. SCH 727965 was selected as a clin. candidate using a functional screen in vivo that integrated both efficacy and safety parameters. Compared with flavopiridol, SCH 727965 exhibits superior activity with an improved therapeutic index. In cell-based assays, SCH 727965 completely suppressed retinoblastoma phosphorylation, which correlated with apoptosis onset and total inhibition of bromodeoxyuridine incorporation in >100 tumor cell lines of diverse origin and background. Moreover, short exposures to SCH 727965 were sufficient for long-lasting cellular effects. SCH 727965 induced regression of established solid tumors in a range of mouse models following intermittent scheduling of doses below the maximally tolerated level. This was assocd. with modulation of pharmacodynamic biomarkers in skin punch biopsies and rapidly reversible, mechanism-based effects on hematol. parameters. These results suggest that SCH 727965 is a potent and selective CDK inhibitor and a novel cytotoxic agent. |