Aurone derivatives as Vps34 inhibitors that modulate autophagy

Guodong Li, Joshua William Boyle, Chung Nga Ko, Wu Zeng, Vincent Kam Wai Wong, Jian Bo Wan, Philip Wai Hong Chan*, Edmond Dik Lung MA, Chung Hang Leung

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)537-544
Number of pages8
JournalActa Pharmaceutica Sinica B
Volume9
Issue number3
DOIs
Publication statusPublished - May 2019

Scopus Subject Areas

  • Pharmacology, Toxicology and Pharmaceutics(all)

User-Defined Keywords

  • Aurone derivative
  • Autophagy
  • Heart or liver damage
  • Inhibitor
  • Natural products
  • Structure-based virtual screening
  • Vesicle trafficking
  • Vps34

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