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Discovery of 2,4-dimethoxypyridines as novel autophagy inhibitors

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Robke, L 
Rodrigues, T 
Schröder, P 
Foley, DJ 
Bernardes, GJL 

Abstract

© 2018 Elsevier Ltd Autophagy is a catabolic process, which mediates degradation of cellular components and has important roles in health and disease. Therefore, small molecule modulators of autophagy are in great demand. Herein, we describe a phenotypic high-content screen for autophagy inhibitors, which led to the discovery of a dimethoxypyridine-based class of autophagy inhibitors, which derive from previously reported, natural product-inspired MAP4K4 inhibitors. Comprehensive structure-activity relationship studies led to a potent compound, and biological validation experiments indicated that the mode of action was upstream or independent of mTOR.

Description

Keywords

Autophagy, Phenotypic screening, High-throughput screening, Natural products, Medicinal chemistry

Journal Title

Tetrahedron

Conference Name

Journal ISSN

0040-4020
1464-5416

Volume Title

74

Publisher

Elsevier BV
Sponsorship
Royal Society (URF\R\180019)
European Commission (EC) (852985)