Development of Autophagy Modulators to Identify Novel Strategies to Treat Cancer and Neurodegeneration

Autophagy is a catabolic process that helps maintain cellular homeostasis by degrading cellular contents via lysosome(s) and has been implicated in a variety of diseases, including inflammatory diseases, neurodegenerative diseases, and cancer. As a result, modulation of this pathway has emerged as a promising therapeutic strategy to treat various human diseases. Our work is centered around the identification of small-molecule autophagy modulators using both target-based and phenotype-based high-throughput screening methods. Current FDA-approved agents that inhibit autophagy include chloroquine (CQ) and hydroxychloroquine (HCQ) which inhibit autophagy at a late stage and lack specificity for the autophagy pathway, resulting in a variety of off-target effects. Our target-based approaches have aimed at identifying and synthetically optimizing selective autophagy inhibitors of the ATG5-ATG16L1-N interaction to assess their potential as a cancer therapeutic strategy. Currently there are few treatments available for Alzheimer’s Disease (AD) and Niemann-Pick Disease (NPC) and treatments for these diseases at the clinical level lack efficacy. Through our phenotypic screening efforts, our lab has focused on the discovery of small-molecule autophagy modulators to study the role of this pathway in AD and NPC. Phenotypic screening is agnostic to targets; therefore, the use of phenotypic methods to discover autophagy modulators requires subsequent target identification and validation experiments. Our efforts in developing new autophagy modulators and identifying their targets have allowed for the exploration of alternative therapeutic approaches for AD and NPC.