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

被引：41

作者：

Bosc, D. ^{[1
,9
]}

Vezenkov, L. ^{[1
,10
]}

Bortnik, S. ^{[2
,3
]}

An, J. ^{[2
]}

Xu, J. ^{[2
,4
]}

Choutka, C. ^{[2
,4
]}

Hannigan, A. M. ^{[2
]}

Kovacic, S. ^{[1
]}

Loo, S. ^{[1
]}

Clark, P. G. K. ^{[1
]}

Chen, G. ^{[1
]}

Guay-Ross, R. N. ^{[1
]}

Yang, K. ^{[2
,4
]}

Dragowska, W. H. ^{[5
]}

Zhang, F. ^{[6
,7
]}

Go, N. E. ^{[2
]}

Leung, A. ^{[2
]}

Honson, N. S. ^{[8
]}

Pfeifer, T. A. ^{[8
]}

Gleave, M. ^{[6
,7
]}

Bally, M. ^{[5
]}

Jones, S. J. ^{[2
,3
,4
]}

Gorski, S. M. ^{[2
,3
,4
]}

Young, R. N. ^{[1
]}

机构：

[1] Simon Fraser Univ, Dept Chem, Burnaby, BC V5A 1S6, Canada

[2] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4E6, Canada

[3] Univ British Columbia, Interdisciplinary Oncol Program, Vancouver, BC, Canada

[4] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada

[5] BC Canc Agcy, Expt Therapeut, Vancouver, BC V5Z 4E6, Canada

[6] Univ British Columbia, Dept Urol Sci, Vancouver, BC V6H 3Z6, Canada

[7] Univ British Columbia, Vancouver Prostate Ctr, Vancouver, BC V6H 3Z6, Canada

[8] Ctr Drug Res & Dev, 2405 Wesbrook Mall,4th Floor, Vancouver, BC V6T 1Z3, Canada

[9] Univ Lille, Inst Pasteur Lille, INSERM, Drugs & Mol Living Syst U1177, F-59000 Lille, France

[10] Univ Montpellier, CNRS UMR 5247, IBMM, ENSCM,Fac Pharm, 15 Ave Charles Flahault, F-34093 Montpellier, France

来源：

SCIENTIFIC REPORTS | 2018年 / 8卷

基金：

加拿大自然科学与工程研究理事会; 加拿大健康研究院;

关键词：

THERAPEUTIC TARGET; ENZYME; LC3; IDENTIFICATION; CHEMOTHERAPY; DEGRADATION; HOMEOSTASIS; DISCOVERY; DOCKING; ASSAYS;

D O I：

10.1038/s41598-018-29900-x

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：17

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