Pharmacological Targeting of Executioner Proteins: Controlling Life and Death
Justin Pogmore, David Uehling, David W. Andrews
Abstract
Small-molecule mediated modulation of protein interactions of Bcl-2 (B-cell lymphoma-2) family proteins was clinically validated in 2015 when Venetoclax, a selective inhibitor of the antiapoptotic protein BCL-2, achieved breakthrough status designation by the FDA for treatment of lymphoid malignancies. Since then, substantial progress has been made in identifying inhibitors of other interactions of antiapoptosis proteins. However, targeting their pro-apoptotic counterparts, the "executioners" BAX, BAK, and BOK that both initiate and commit the cell to dying, has lagged behind. However, recent publications demonstrate that these proteins can be positively or negatively regulated using small molecule tool compounds. The results obtained with these molecules suggest that pharmaceutical regulation of apoptosis will have broad implications that extend beyond activating cell death in cancer. We review recent advances in identifying compounds and their utility in the exogenous control of life and death by regulating executioner proteins, with emphasis on the prototype BAX.