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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9a9e47719cda4bf8a6d913a40f60c964
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spelling	oai:doaj.org-article:9a9e47719cda4bf8a6d913a40f60c9642021-12-02T15:07:44ZA new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B10.1038/s41598-018-29900-x2045-2322https://doaj.org/article/9a9e47719cda4bf8a6d913a40f60c9642018-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-29900-xhttps://doaj.org/toc/2045-2322Abstract 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.D. BoscL. VezenkovS. BortnikJ. AnJ. XuC. ChoutkaA. M. HanniganS. KovacicS. LooP. G. K. ClarkG. ChenR. N. Guay-RossK. YangW. H. DragowskaF. ZhangN. E. GoA. LeungN. S. HonsonT. A. PfeiferM. GleaveM. BallyS. J. JonesS. M. GorskiR. N. YoungNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-17 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
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
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 Portfolio
publishDate	2018
url	https://doaj.org/article/9a9e47719cda4bf8a6d913a40f60c964
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A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B

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