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; Dik-Lung Ma; Chung-Hang Leung

doi:10.1016/j.apsb.2019.01.016

Aurone derivatives as Vps34 inhibitors that modulate autophagy

Acta Pharm Sin B. 2019 May;9(3):537-544. doi: 10.1016/j.apsb.2019.01.016. Epub 2019 Jan 30.

Authors

Guodong Li¹, Joshua William Boyle², Chung-Nga Ko³, Wu Zeng⁴, Vincent Kam Wai Wong⁴, Jian-Bo Wan¹, Philip Wai Hong Chan^{2

5}, Dik-Lung Ma³, Chung-Hang Leung¹

Affiliations

¹ State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China.
² School of Chemistry, Monash University, Clayton 3800, Australia.
³ Department of Chemistry, Hong Kong Baptist University, Hong Kong 999077, China.
⁴ State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China.
⁵ Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.

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.

Keywords: Aurone derivative; Autophagy; CETSA, cellular thermal shift assay; Co-IP, co-immunoprecipitation; DMEM, Dulbecco׳s modified Eagle׳s medium; DMSO, dimethyl sulfoxide; EBSS, Earle׳s balanced salt solution; ELISA, enzyme-linked immunosorbent assay; FBS, fetal bovine serum; Heart or liver damage; Inhibitor; Natural products; PE, phosphatidylethanolamine; PI, phosphatidylinositol; PI3K, phosphoinositide 3-kinase; PI3P, phosphatidylinositol 3-phosphate; PS, phosphatidylserine; Structure-based virtual screening; Vesicle trafficking; Vps34.