A New Quinoline-Based Chemical Probe Inhibits the Autophagy-Related Cysteine Protease ATG4B

Peer reviewed: 
Yes, item is peer reviewed.
Scholarly level: 
Faculty/Staff
Final version published as: 

osc, D., Vezenkov, L., Bortnik, S. et al. A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B. Sci Rep 8, 11653 (2018). DOI: 10.1038/s41598-018-29900-x.

Date created: 
2018-08-03
Keywords: 
Proteases
Virtual screening
Abstract: 

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.

Language: 
English
Document type: 
Article
File(s): 
Sponsor(s): 
Canadian Institutes of Health Research (CIHR)
Natural Sciences and Engineering Research Council of Canada (NSERC)
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