Pro-apoptotic BCL-2 family member BAX is a critical effector of the mitochondrial cell death pathway in response to a diverse range of stimuli in physiological and disease contexts. Cytosolic and inactive BAX, upon conformational activation by BH3-only proteins, translocates and oligomerizes at the mitochondrial outer membrane to assemble a lethal pore that initiates apoptosis. Additionally, BAX has been linked in the regulation of necrotic cell death, a function that requires BAX mitochondrial translocation but no oligomerization.Efforts to rationally target BAX and develop inhibitors have been challenged by the conformational dynamic nature of BAX despite the promising therapeutic potential of inhibiting BAX-mediated cell death in a host of diseases. Here, I will discuss the discovery of small molecule allosteric BAX inhibitors, termed BAX activation inhibitors (BAIs), using NMR studies and biochemical methods to screen and characterize their allosteric mechanism of action. BAIs bind directly to a previously unrecognized pocket of inactive BAX, inhibiting BAX activation without competing with activators of BAX to bind its activation site. Using NMR, mutagenesis and structure-activity relationship studies, we demonstrate that BAI-binding around the hydrophobic helix α5 includes hydrophobic and hydrogen-bonding interactions that stabilize key areas of the hydrophobic core and allosterically inhibit BAX conformational activation. This effect prevents BAX mitochondrial translocation and oligomerization leading to inhibition of BAX-dependent apoptosis and necrosis from different death stimuli. <i>In vivo</i>, our lead inhibitor protects the hearts of mice from doxorubicin-induced cardiomyopathy. Importantly, protection of the heart does not compromise the efficacy of doxorubicin to reduce breast cancer or leukemia burden in several <i>in vivo </i>models. Our findings identified a novel mechanism and allosteric inhibitors for rational and selective pharmacological inhibition of BAX in doxorubicin-induced cardiomyopathy and potentially other diseases of deregulated BAX-mediated cell death.

Discovery of first-in-class allosteric inhibitors of BAX

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.