Discovery of 2, 4-dimethoxypyridines as novel autophagy inhibitors. Issue 35 (30th August 2018)

• Record Type: Journal Article
• Authors: Robke, Lucas; Rodrigues, Tiago; Schröder, Peter; Foley, Daniel J.; Bernardes, Gonçalo J.L.; Laraia, Luca; Waldmann, Herbert
• Is Part Of: Tetrahedron. Volume 74:Issue 35(2018)
• Page Start: 4531
• Page End: 4537
• Publication Date: 2018-08-30
• Subjects: Autophagy -- Phenotypic screening -- High-throughput screening -- Natural products -- Medicinal chemistry; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2018.07.021
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: 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. Graphical abstract: