TY - JOUR
T1 - Discovery of 2,4-dimethoxypyridines as novel autophagy inhibitors
AU - Robke, Lucas
AU - Rodrigues, Tiago
AU - Schröder, Peter
AU - Foley, Daniel J.
AU - Bernardes, Gonçalo J.L.
AU - Laraia, Luca
AU - Waldmann, Herbert
PY - 2018
Y1 - 2018
N2 - 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
AB - 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
KW - Autophagy
KW - Phenotypic screening
KW - High-throughput screening
KW - Natural products
KW - Medicinal chemistry
U2 - 10.1016/j.tet.2018.07.021
DO - 10.1016/j.tet.2018.07.021
M3 - Journal article
SN - 0040-4020
VL - 74
SP - 4531
EP - 4537
JO - Tetrahedron
JF - Tetrahedron
ER -