Direct Targeting of Pro-Apoptotic BAX as a Novel Strategy for Cancer Therapy

Abstract

Resistance to apoptosis is a hallmark of cancer. The BCL-2 protein family contains anti-and pro-apoptotic members that regulate mitochondria) apoptosis. Cancer cells ensure their survival and resistance to treatments by overexpression of anti-apoptotic BCL-2 proteins to maintain pro-apoptotic BAX and other pro-apoptotic members suppressed. Therapeutic strategies to selectively activate apoptosis in cancer have focused on inhibiting anti-apoptotic BCL-2 proteins. Here, we used a pharmacophore model and medicinal chemistry to rationally design BAX trigger site binders based on previous structural models of the BIM BH3 helix and BAM7 compound. We have identified the discovery of BTSA1, a pharmacologically optimized BAX activator that binds with high affinity and specificity to the N-terminal trigger site and induces conformational changes on BAX leading to BAX-mediated apoptosis. BTSA1-induced BAX activation effectively promotes apoptosis in leukemia cell lines and patient samples while sparing healthy cells. BAX expression levels and cytosolic conformation regulate sensitivity to BTSA1. BTSA1 potently suppressed human acute myeloid leukemia (AML) xenografts and increased host survival without toxicity. Our results demonstrate that direct BAX activation by BTSA1 promotes selective apoptosis and efficacious anti-tumor activity without adversely affecting healthy cells. This study provides insights for the therapeutic potential of direct BAX activation in AML and potentially other cancers.