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Molecules 2017, 22(6), 891;

Identification of Novel Vacuolin-1 Analogues as Autophagy Inhibitors by Virtual Drug Screening and Chemical Synthesis

State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
City University of Hong Kong Shen Zhen Research Institute, Shenzhen 518057, China
Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China
Equal contribution.
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 26 April 2017 / Revised: 25 May 2017 / Accepted: 25 May 2017 / Published: 27 May 2017
(This article belongs to the Section Medicinal Chemistry)
Full-Text   |   PDF [3806 KB, uploaded 2 June 2017]   |  


Autophagy is a fundamental cellular degradation process which is essential for cell homeostasis, and dysfunctional autophagy has been associated with a variety of human diseases, such as cancer. Several autophagy chemical modulators have been applied in a number of preclinical or clinical trials against these autophagy related diseases, especially cancer. Small molecule vacuolin-1 potently and reversibly inhibits both endosomal-lysosomal trafficking and autophagosome-lysosome fusion, yet the molecular mechanisms underlying vacuolin-1 mediated autophagy inhibition remain unknown. Here, we first performed the virtual drug screening and identified 14 vacuolin-1 analogues as autophagy inhibitors. Based on these virtual screening results, we further designed and synthesized 17 vacuolin-1 analogues, and found that 13 of them are autophagy inhibitors and a couple of them are as potent as vacuolin-1. In summary, these studies expanded the pool of useful autophagy inhibitors and reveal the structural-activity relationship of vacuolin-1 analogues, which is useful for future development of vacuolin-1 analogues with high potency and for identification of the molecular targets of vacuolin-1. View Full-Text
Keywords: autophagy; vacuolin-1; LC3B-II; SAR; inhibitor autophagy; vacuolin-1; LC3B-II; SAR; inhibitor

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    Doi: 10.4161/auto.32200

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Chen, C.; Lu, Y.; Siu, H.M.; Guan, J.; Zhu, L.; Zhang, S.; Yue, J.; Zhang, L. Identification of Novel Vacuolin-1 Analogues as Autophagy Inhibitors by Virtual Drug Screening and Chemical Synthesis. Molecules 2017, 22, 891.

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