Pro-apoptotic Bax/Bak proteins are key regulators of the intrinsic apoptosis pathway. The oligomerization of these proteins within the mitochondrial outer membrane is directly responsible for the pore formation in the membrane, which causes cell death. The therapeutic potential of anti-apoptotic Bcl-2 inhibitors as anticancer agents has been extensively studied, while there are no potent and selective inhibitors to pro-apoptotic Bax/Bak, which could lead to the development of neuroprotective agents. Therefore, the goal of this project is to develop potent and selective small-molecule inhibitors for pro-apoptotic Bax/Bak proteins. Our preliminary docking calculations and biological evaluation suggest that ABT-199 and ABT-263, two anti-tumor drugs, bind weakly to Bax proteins. Building upon these preliminary findings, we will design a library of ABT-199/263 analogs, which will be assessed using fluorescence, crosslinking, and pore-forming assays in vitro. The identified potent and selective Bax inhibitors will be evaluated in cells for their anti-apoptotic activity. Findings from these studies will facilitate both basic and applied apoptosis research, and provide a platform for the development of neuro/cardio-protective agents.