This family of pro-survival proteins, which includes Bcl-2, Bcl-xL and Mcl-1, repress apoptosis and are commonly over-expressed in human cancers. Bcl-2 proteins are well documented to be associated with the maintenance and progression of tumors. Additionally, these proteins are closely associated with resistance to existing chemotherapies. Therefore, antagonizing the activity of Bcl-2 family members can have a direct impact on tumor progression, as well as improving the efficacy of established, clinically important chemotherapeutic regimens.
There are a number of drug candidates currently in clinical trials for this target. Abbott and Idun Pharmaceuticals participated in a novel drug discovery program to identify small molecule "fragments" that interfere with protein-protein interactions, specifically interactions with the BH3 binding groove of Bcl-xL (A in figure below). The BH3 binding domain is a large hydrophobic pocket and is the region where cognate proteins bind. Binding to this domain is a prerequisite for the pro-survival activity of all Bcl-2 family members. Extensive in vitro optimization, including detailed mechanism of action studies coupled with comprehensive characterization in animal models of cancer, led to the advanced development lead ABT-737 (B in figure below), and ultimately to the selection of a Bcl-2 inhibitor for clinical development. The selected clinical compound is currently under clinical evaluation in over a dozen Phase 1 and Phase 2 clinical trials, including various solid tumors and lymphoid cancers.