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Aurone derivatives as Vps34 inhibitors that modulate autophagy.

ABSTRACT: 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.

SUBMITTER: Li G

PROVIDER: S-EPMC6543056 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Aurone derivatives as Vps34 inhibitors that modulate autophagy.

Li Guodong G Boyle Joshua William JW Ko Chung-Nga CN Zeng Wu W Wong Vincent Kam Wai VKW Wan Jian-Bo JB Chan Philip Wai Hong PWH Ma Dik-Lung DL Leung Chung-Hang CH

Acta pharmaceutica Sinica. B 20190130 3

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 inhibi ...[more]

PMID: 31193773

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