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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.
Afiliação
  • Bosc D; Department of Chemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada.
  • Vezenkov L; Inserm, Institut Pasteur de Lille, U1177 Drugs & Molecules for Living Systems, Université de Lille, F-59000, Lille, France.
  • Bortnik S; Department of Chemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada.
  • An J; Institut des Biomolécules Max Mousseron (IBMM), UMR 5247 CNRS, Université de Montpellier, ENSCM, Faculté de Pharmacie, 15 avenue Charles Flahault, 34093, Montpellier, France.
  • Xu J; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada.
  • Choutka C; Interdisciplinary Oncology Program, University of British Columbia, Vancouver, Canada.
  • Hannigan AM; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada.
  • Kovacic S; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada.
  • Loo S; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada.
  • Clark PGK; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada.
  • Chen G; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada.
  • Guay-Ross RN; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada.
  • Yang K; Department of Chemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada.
  • Dragowska WH; Department of Chemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada.
  • Zhang F; Department of Chemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada.
  • Go NE; Department of Chemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada.
  • Leung A; Department of Chemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada.
  • Honson NS; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada.
  • Pfeifer TA; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, V5A 1S6, Canada.
  • Gleave M; Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada.
  • Bally M; Department of Urologic Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H 3Z6, Canada.
  • Jones SJ; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada.
  • Gorski SM; Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, V5Z 4E6, Canada.
  • Young RN; Centre for Drug Research and Development, 2405 Wesbrook Mall - 4th Floor, Vancouver, BC, V6T 1Z3, Canada.
Sci Rep ; 8(1): 11653, 2018 08 03.
Article em En | MEDLINE | ID: mdl-30076329
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Quinolinas / Autofagia / Cisteína Endopeptidases / Proteínas Relacionadas à Autofagia Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Sci Rep Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Canadá

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Quinolinas / Autofagia / Cisteína Endopeptidases / Proteínas Relacionadas à Autofagia Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Revista: Sci Rep Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Canadá