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 non-canonical autophagy-dependent inflammatory cytokine secretion mechanism. 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 disruptors of ATG12-ATG3 protein-protein interaction. A systematic modification of the hit structure led us to a wide plethora of compounds that maintain its ATG12-ATG3 inhibitory activity, which could act as a viable starting point to design new compounds with diverse therapeutic applications.

Department of Molecular Genetics Weizmann Institute of Science Rehovot 76100 Israel

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences 16610 Prague Czech Republic

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences 16610 Prague Czech Republic; Department of Chemistry of Natural Compounds University of Chemistry and Technology Prague 166 28 Prague Czech Republic

The Nancy and Stephen Grand Israel National Center for Personalized Medicine Weizmann Institute of Science Rehovot 76100 Israel

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