In vitro and in vivo characterization of the CDK2 inhibitor PHA-533533

824 The Cyclin Dependent Kinase 2 (CDK2) is a serine threonine kinase. It is heterodimer composed of a catalytic subunit, CDK2, and one of two activating subunits, cyclin E or cyclin A. The two isoforms of the kinase have distinct roles during the cell cycle. CDK2/cyclin E is mainly involved in progression through G1/S, centrosome duplication, and DNA replication. CDK2/cyclin A is a key regulator of the G2/M progression. Observations supporting the use of a CDK2 inhibitors in a clinical setting are abundant: The activating subunits of CDK2, cyclin A and E, are frequently overexpressed in tumors, and a negative regulator of CDK2 activity, p27kip1, is frequently down regulated in tumors. Our hypothesis is that deregulated activity of CDK2 complexes is a contributing factor to tumor cell growth; therefore we expect that the inhibition of the kinase could block the tumor cell proliferation. In the poster, the in vitro and in vivo characterization of the mode of action of a CDK2 inhibitor, PHA-533533, will be presented. In particular, the effects of PHA-533533 on different phases of the cell cycle using synchronized tumor cells. In addition, in vivo efficacy and mode of action data will be presented. The data indicate that activity of PHA-533533 is consistant with that of a CDK2 inhibitor and that inhibition of CDK2 adversely affects tumor cell growth in vitro and in vivo.