Development of Autophagy Modulators and Performance-diverse, Natural Product-inspired Libraries

Autophagy is an evolutionarily conserved catabolic process that contributes to cell physiology and helps maintain cytoplasmic homeostasis. As autophagy modulation has shown promise in the treatment of various human diseases including cancer, obesity, cardiovascular disease, neurodegenerative diseases, and infectious and inflammatory diseases, we have been focused on the development of small-molecule probes to modulate the autophagy pathway and to investigate novel therapeutic strategies for treating diseases. Phenotypic and targeted approaches have been implemented to discover and optimize small-molecule autophagy inhibitors for the treatment of cancer. The phenotypic high-throughput screen identified autophagy inhibitors that could potentially reveal new targets for therapeutic modulation. Synthetic routes have been developed and optimized to generate analogues with higher potency. A targeted approach was also designed to discover small molecules that disrupt the Beclin1-ATG14L protein-protein interaction to selectively inhibit autophagy at an early stage without causing defects in endosomal trafficking. Synthetic routes have been developed to access analogues with improved properties. Small-molecule autophagy modulators that enhance clearance of unesterified cholesterol have also been identified and synthesized for evaluation in Niemann-Pick type C (NPC) disease models. An enantioselective approach to the synthesis of flavanol derivatives from chalcones has been developed to provide an efficient way to prepare diverse natural product-inspired libraries with stereochemical and appendage diversity to systematically evaluate biological performance diversity and to identify predictive trends to reduce redundancy within small-molecule libraries.