Optimization of Small-Molecule Inhibitor of Atg12-Atg3 Protein-Protein Interaction

Abstract

Autophagy is a catabolic process that was described to play a critical role in advanced stages of cancer, wherein it maintains tumor cell homeostasis and growth by supplying nutrients. Autophagy is also described to support alternative cellular trafficking pathways, providing a mechanism of non-canonical autophagy-dependent inflammatory cytokine secretion. Therefore, autophagy inhibitors have high potential in the treatment of cancer and acute inflammation. In our study, we identified compound 1 as an inhibitor of the ATG12-ATG3 protein-protein interaction. We focused on the systematic modification of the original hit 1, a casein kinase 2 (CK2) inhibitor, to find potent inhibitors of autophagy. A systematic modification of the hit structure led us to a wide plethora of compounds that maintains its autophagy inhibitory activity, which could act as a viable starting point for designing new compounds with diverse therapeutic applications.

Keywords: autophagy, autophagy inhibition, small molecule, Protein-protein interaction