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.
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