Discovery of Small-Molecule Autophagy Modulators for the Study of Human Disease

Studies of human genetics and pathophysiology have implicated the regulation of autophagy in inflammation, neurodegeneration, infection, and other disease states. These findings have motivated the development of small-molecule probes with diverse mechanisms of action to study how modulation of autophagy affects disease-associated phenotypes and to evaluate the therapeutic potential of autophagy in human disease.

This seminar will describe the discovery of novel small-molecule probes derived from diversity-oriented synthesis that enhance autophagy through mTOR-independent pathways. Global analysis of high-throughput screening data for 65,000 small molecules identified common structural features associated with autophagy-enhancing activity across distinct chemical scaffolds. The ability of five representative small-molecule autophagy modulators to ameliorate disease phenotypes previously linked to autophagy dysfunction will be presented, including intracellular bacterial replication, inflammatory cytokine production, survival of primary neurons harboring Niemann-Pick type C-associated mutations, and protein aggregation. Our results highlight the potential for small-molecule probes of autophagy to provide a better understanding of human health and disease.