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The cysteine protease ATG4B is a key component of the autophagy machinery, acting to proteolytically prime and recycle its substrate MAP1LC3B. The roles of ATG4B in cancer and other diseases appear to be context dependent but are still not well understood. To help further explore ATG4B functions and potential therapeutic applications, we employed a chemical biology approach to identify ATG4B inhibitors. Here, we describe the discovery of  4–28 , a styrylquinoline identified by a combined computational modeling,  in silico  screening, high content cell-based screening and biochemical assay approach. A structure-activity relationship study led to the development of a more stable and potent compound  LV-320 . We demonstrated that  LV-320  inhibits ATG4B enzymatic activity, blocks autophagic flux in cells, and is stable, non-toxic and active  in vivo . These findings suggest that  LV-320  will serve as a relevant chemical tool to study the various roles of ATG4B in cancer and other contexts.

A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B