Targeting key apoptosis regulators to overcome the apoptotic resistance of cancer cells is a highly attractive therapeutic strategy. The BCL-2 protein family includes both pro- and anti-apoptotic proteins that form a complex interaction network and regulate the critical balance between cellular life and death. BAX is a pro-apoptotic BCL-2 member that, when activated, undergoes a structural transformation, which converts BAX from an inactive cytosolic conformation into a lethal mitochondrial pore. Anti-apoptotic BCL-2 members contribute to the development, maintenance, and chemoresistance of human cancers by suppressing their pro-apoptotic counterparts. Therefore, the vast majority of cancer cells contain functional but suppressed BAX. We previously identified structural regions of BAX involved in the regulation of its activation, including the N-terminal activation site, and small molecules that trigger BAX activation, providing a new opportunity for rational drug design to target BAX (Nature, 2008. PMID: 18948948, Mol. Cell, 2010. PMID: 21070973, Nat. Chem. Biol., 2012. PMID: 22634637). Here, we will report our chemical biology, structure-based design and medicinal chemistry efforts to optimize our compounds to selectively and potently bind the BAX activation site and promote functional BAX oligomerization and BAX-mediated cell death to in vitro and in vivo models of human Acute Myeloid Leukemia. Our data highlight that the combination of chemical and structural biology approaches successfully accomplishes targeting of a challenging protein-protein interaction that requires to undergo allosteric conformational activation. Moreover, we identified the first-in-class compounds that can induce apoptosis in cancer cells while sparing healthy cells, through direct and selective interaction with BAX, providing a lead compound for development into a next generation cancer therapeutic.

Small molecule activators of Pro-apoptotic BAX for cancer therapy

249th National Meeting (2015)

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