Autophagy is a cellular process that maintains homeostasis through degradation and recycling of cellular components. In cancer cells, autophagy can promote survival by providing a mechanism to overcome cellular stress from nutrient deprivation, hypoxia, or chemotherapy. Chloroquine and hydroxychloroquine, which impact lysosome function, are commonly used to evaluate the role of autophagy in cancer, but these small molecules are not selective for the autophagy pathway. The development of selective small-molecule inhibitors of the autophagy pathway will enable the study of this pathway in cancer and the determination of which types of cancers may be sensitive to selective autophagy inhibition. Our lab has recently developed a high-throughput fluorescence polarization assay to identify small molecules that disrupt the protein-protein interaction between ATG5 and ATG16L1 to prevent lipidation of LC3-I to inhibit autophagosome formation. We identified two inhibitors using this target-based assay, but they did not show significant activity in cells, potentially due to their lack of solubility and moderate potency. Our current focus is the development of synthetic strategies to access both of these hits and analogues to improve potency and properties to enable evaluation of ATG5-ATG16L1 protein-protein interaction inhibitors in cancer cells.

Development of autophagy inhibitors that target the ATG5-ATG16L1 protein-protein interaction

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.