Aurone derivatives as Vps34 inhibitors that modulate autophagy

摘要

We report in this study the identification of a natural product-like antagonist (1a) of Vps34 as a potent autophagy modulator via structure-based virtual screening.Aurone derivative 1a strongly inhibited Vps34 activity in cell-free and cell-based assays.Significantly,1a prevents autophagy in human cells induced either by starvation or by an mTOR inhibitor.In silico modeling and kinetic data revealed that 1a could function as an ATP-competitive inhibitor of Vps34.Moreover,it suppressed autophagy in vivo and without inducing heart or liver damage in mice.1a could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases.