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Aurone derivatives as Vps34 inhibitors that modulate autophagy
Guodong Li1; Joshua William Boyle2; Chung-Nga Ko3; Wu Zeng4; Vincent Kam Wai Wong4; Jian-Bo Wan1; Philip Wai Hong Chan2,5; Dik-Lung Ma3; Chung-Hang Leung1
2019-05
Source PublicationACTA PHARMACEUTICA SINICA B
ISSN2211-3835
Volume9Issue:3Pages:537-544
Abstract

We report in this study the identification of a natural product-like antagonist (la) of Vps34 as a potent autophagy modulator via structure-based virtual screening. Aurone derivative la strongly inhibited Vps34 activity in cell-free and cell-based assays. Significantly, la prevents autophagy in human cells induced either by starvation or by an mTOR inhibitor. In silico modeling and kinetic data revealed that la could function as an ATP-competitive inhibitor of Vps34. Moreover, it suppressed autophagy in vivo and without inducing heart or liver damage in mice. la could be utilized as a new motif for more selective and efficacious antagonists of Vps34 for the potential treatment of autophagy-related human diseases. (C) 2019 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.

KeywordAutophagy Natural Products Vps34 Inhibitor Structure-based Virtualscreening Vesicle Trafficking Heart Or Liver Damage Aurone Derivative
DOI10.1016/j.apsb.2019.01.016
Indexed BySCI
Language英语
WOS Research AreaPharmacology & Pharmacy
WOS SubjectPharmacology & Pharmacy
WOS IDWOS:000469394400008
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Cited Times [WOS]:2   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Affiliation1.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
First Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Guodong Li,Joshua William Boyle,Chung-Nga Ko,et al. Aurone derivatives as Vps34 inhibitors that modulate autophagy[J]. ACTA PHARMACEUTICA SINICA B,2019,9(3):537-544.
APA Guodong Li.,Joshua William Boyle.,Chung-Nga Ko.,Wu Zeng.,Vincent Kam Wai Wong.,...&Chung-Hang Leung.(2019).Aurone derivatives as Vps34 inhibitors that modulate autophagy.ACTA PHARMACEUTICA SINICA B,9(3),537-544.
MLA Guodong Li,et al."Aurone derivatives as Vps34 inhibitors that modulate autophagy".ACTA PHARMACEUTICA SINICA B 9.3(2019):537-544.
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