A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B
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 func...
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Nature Publishing Group
2018-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-018-29900-x |
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doaj-9a9e47719cda4bf8a6d913a40f60c9642020-12-08T03:41:16ZengNature Publishing GroupScientific Reports2045-23222018-08-018111710.1038/s41598-018-29900-xA new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4BD. Bosc0L. Vezenkov1S. Bortnik2J. An3J. Xu4C. Choutka5A. M. Hannigan6S. Kovacic7S. Loo8P. G. K. Clark9G. Chen10R. N. Guay-Ross11K. Yang12W. H. Dragowska13F. Zhang14N. E. Go15A. Leung16N. S. Honson17T. A. Pfeifer18M. Gleave19M. Bally20S. J. Jones21S. M. Gorski22R. N. Young23Department of Chemistry, Simon Fraser UniversityDepartment of Chemistry, Simon Fraser UniversityCanada’s Michael Smith Genome Sciences Centre, BC Cancer AgencyCanada’s Michael Smith Genome Sciences Centre, BC Cancer AgencyCanada’s Michael Smith Genome Sciences Centre, BC Cancer AgencyCanada’s Michael Smith Genome Sciences Centre, BC Cancer AgencyCanada’s Michael Smith Genome Sciences Centre, BC Cancer AgencyDepartment of Chemistry, Simon Fraser UniversityDepartment of Chemistry, Simon Fraser UniversityDepartment of Chemistry, Simon Fraser UniversityDepartment of Chemistry, Simon Fraser UniversityDepartment of Chemistry, Simon Fraser UniversityCanada’s Michael Smith Genome Sciences Centre, BC Cancer AgencyExperimental Therapeutics, BC Cancer AgencyDepartment of Urologic Sciences and Vancouver Prostate Centre, University of British ColumbiaCanada’s Michael Smith Genome Sciences Centre, BC Cancer AgencyCanada’s Michael Smith Genome Sciences Centre, BC Cancer AgencyCentre for Drug Research and DevelopmentCentre for Drug Research and DevelopmentDepartment of Urologic Sciences and Vancouver Prostate Centre, University of British ColumbiaExperimental Therapeutics, BC Cancer AgencyCanada’s Michael Smith Genome Sciences Centre, BC Cancer AgencyCanada’s Michael Smith Genome Sciences Centre, BC Cancer AgencyDepartment of Chemistry, Simon Fraser UniversityAbstract 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.https://doi.org/10.1038/s41598-018-29900-x |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
D. Bosc L. Vezenkov S. Bortnik J. An J. Xu C. Choutka A. M. Hannigan S. Kovacic S. Loo P. G. K. Clark G. Chen R. N. Guay-Ross K. Yang W. H. Dragowska F. Zhang N. E. Go A. Leung N. S. Honson T. A. Pfeifer M. Gleave M. Bally S. J. Jones S. M. Gorski R. N. Young |
| spellingShingle |
D. Bosc L. Vezenkov S. Bortnik J. An J. Xu C. Choutka A. M. Hannigan S. Kovacic S. Loo P. G. K. Clark G. Chen R. N. Guay-Ross K. Yang W. H. Dragowska F. Zhang N. E. Go A. Leung N. S. Honson T. A. Pfeifer M. Gleave M. Bally S. J. Jones S. M. Gorski R. N. Young A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B Scientific Reports |
| author_facet |
D. Bosc L. Vezenkov S. Bortnik J. An J. Xu C. Choutka A. M. Hannigan S. Kovacic S. Loo P. G. K. Clark G. Chen R. N. Guay-Ross K. Yang W. H. Dragowska F. Zhang N. E. Go A. Leung N. S. Honson T. A. Pfeifer M. Gleave M. Bally S. J. Jones S. M. Gorski R. N. Young |
| author_sort |
D. Bosc |
| title |
A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B |
| title_short |
A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B |
| title_full |
A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B |
| title_fullStr |
A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B |
| title_full_unstemmed |
A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B |
| title_sort |
new quinoline-based chemical probe inhibits the autophagy-related cysteine protease atg4b |
| publisher |
Nature Publishing Group |
| series |
Scientific Reports |
| issn |
2045-2322 |
| publishDate |
2018-08-01 |
| description |
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. |
| url |
https://doi.org/10.1038/s41598-018-29900-x |
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