Autophagy is a catabolic degradation process that recycles cellular components to maintain homeostasis. Cancer cells can utilize autophagy for survival in hypoxic and nutrient-deprived environments, and thus selective autophagy inhibition could potentially prevent tumor progression. Chloroquine and its analogue, hydroxychloroquine, have been used to inhibit autophagy in clinical trials for cancer, but these compounds disrupt lysosome function and are not selective for the autophagy pathway. We hypothesized that inhibition of the ATG14L-Beclin1 protein-protein interaction, which is exclusive to the VPS34 autophagy initiation complex, would selectively inhibit autophagy, and our lab recently identified compound 19 which supports this hypothesis. We have successfully developed a four-step synthetic route to generate reverse sulfonamide analogues of compound 19. Our current focus is the iterative synthesis and evaluation of compound 19 analogues to improve potency and solubility of the original hit. Compounds with improved activity and properties will enable the evaluation of this novel therapeutic strategy in cancer cell lines and animal models.

Synthesis of reverse sulfonamide analogues of an ATG14L-Beclin1 protein-protein interaction inhibitor

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.