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

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...

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Autores principales: Bosc, D., Vezenkov, L., Bortnik, S., An, J., Xu, J., Choutka, C., Hannigan, A. M., Kovacic, S., Loo, S., Clark, P. G. K., Chen, G., Guay-Ross, R. N., Yang, K., Dragowska, W. H., Zhang, F., Go, N. E., Leung, A., Honson, N. S., Pfeifer, T. A., Gleave, M., Bally, M., Jones, S. J., Gorski, S. M., Young, R. N.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076261/
https://www.ncbi.nlm.nih.gov/pubmed/30076329
http://dx.doi.org/10.1038/s41598-018-29900-x
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author Bosc, D.
Vezenkov, L.
Bortnik, S.
An, J.
Xu, J.
Choutka, C.
Hannigan, A. M.
Kovacic, S.
Loo, S.
Clark, P. G. K.
Chen, G.
Guay-Ross, R. N.
Yang, K.
Dragowska, W. H.
Zhang, F.
Go, N. E.
Leung, A.
Honson, N. S.
Pfeifer, T. A.
Gleave, M.
Bally, M.
Jones, S. J.
Gorski, S. M.
Young, R. N.
author_facet Bosc, D.
Vezenkov, L.
Bortnik, S.
An, J.
Xu, J.
Choutka, C.
Hannigan, A. M.
Kovacic, S.
Loo, S.
Clark, P. G. K.
Chen, G.
Guay-Ross, R. N.
Yang, K.
Dragowska, W. H.
Zhang, F.
Go, N. E.
Leung, A.
Honson, N. S.
Pfeifer, T. A.
Gleave, M.
Bally, M.
Jones, S. J.
Gorski, S. M.
Young, R. N.
author_sort Bosc, D.
collection PubMed
description 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.
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spelling pubmed-60762612018-08-07 A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B Bosc, D. Vezenkov, L. Bortnik, S. An, J. Xu, J. Choutka, C. Hannigan, A. M. Kovacic, S. Loo, S. Clark, P. G. K. Chen, G. Guay-Ross, R. N. Yang, K. Dragowska, W. H. Zhang, F. Go, N. E. Leung, A. Honson, N. S. Pfeifer, T. A. Gleave, M. Bally, M. Jones, S. J. Gorski, S. M. Young, R. N. Sci Rep Article 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. Nature Publishing Group UK 2018-08-03 /pmc/articles/PMC6076261/ /pubmed/30076329 http://dx.doi.org/10.1038/s41598-018-29900-x Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Bosc, D.
Vezenkov, L.
Bortnik, S.
An, J.
Xu, J.
Choutka, C.
Hannigan, A. M.
Kovacic, S.
Loo, S.
Clark, P. G. K.
Chen, G.
Guay-Ross, R. N.
Yang, K.
Dragowska, W. H.
Zhang, F.
Go, N. E.
Leung, A.
Honson, N. S.
Pfeifer, T. A.
Gleave, M.
Bally, M.
Jones, S. J.
Gorski, S. M.
Young, R. N.
A new quinoline-based chemical probe inhibits the autophagy-related cysteine protease ATG4B
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076261/
https://www.ncbi.nlm.nih.gov/pubmed/30076329
http://dx.doi.org/10.1038/s41598-018-29900-x
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