Novel Bcl‑2 Inhibitors Selectively Disrupt the Autophagy-Specific Bcl-2–Beclin 1 Protein–Protein Interaction

Autophagy plays essential roles in a wide variety of physiological processes, such as cellular homeostasis, metabolism, development, differentiation, and immunity. Selective pharmacological modulation of autophagy is considered a valuable potential therapeutic approach to treat diverse human diseases. However, development of such therapies has been greatly impeded by the lack of specific small molecule autophagy modulators. Here, we performed structure–activity relationship studies on a previously discovered weak Bcl-2 inhibitor SW076956, and developed a panel of small molecule compounds that selectively released Bcl-2-mediated inhibition of autophagy-related Beclin 1 compared to apoptosis-related Bax at nanomolar concentration. Our NMR analysis showed that compound 35 directly binds Bcl-2 and specifically inhibits the interaction between the Bcl-2 and Beclin 1 BH3 domains without disruption of the Bcl-2–Bax BH3 interaction. More broadly, this proof-of-concept study demonstrates that targeting protein–protein interactions of the intrinsic autophagy regulatory network can serve as a valuable strategy for the development of autophagy-based therapeutics.