In vitro profiling of UCB1350883, a novel, highly selective antagonist of Bcl-2

B297 The establishment and maintenance of tumours is reliant in part on the ability of tumour cells to evade apoptosis. Resistance to anticancer agents can also be mediated by the failure of treated cells to undergo apoptosis. The anti-apoptotic members of the Bcl-2 protein family play a key role in suppressing apoptosis by sequestering and neutralizing pro-apoptotic members of the family. We describe UCB1350883, a small molecule antagonist of Bcl-2 function, and its biological activity. UCB1350883 binds the BH3-binding groove of Bcl-2 and is greater than 10-fold selective for Bcl-2 over Bcl-X L , Bcl-w and Mcl-1. The inhibitor shows target-based activity in a Bcl-2-dependent mechanistic cell assay and is able to disrupt endogenous Bcl-2 complexes. We present in vitro data demonstrating the activity of UCB1350883 both alone and in combination with anti-cancer agents in tumour cell growth inhibition assays. This is the first report of a potent and selective Bcl-2 inhibitor; we discuss the importance of the inhibitory profile of compounds targeted against Bcl-2 family proteins with respect to their biological activity.