期刊
MOLECULES
卷 22, 期 6, 页码 -出版社
MDPI AG
DOI: 10.3390/molecules22060891
关键词
autophagy; vacuolin-1; LC3B-II; SAR; inhibitor
资金
- Hong Kong Research Grant Council (RGC) [785213, 17126614]
- CAS-Croucher Funding Scheme
- Guangdong-Hong Kong joint innovation Research Scheme [2016A050503010]
- Shenzhen government research grant [JCYJ20160229165235739]
- National Natural Science Foundation of China (NSFC) [31501116, 91213302, 81673279]
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.
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