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Updated: Jul 29, 2026
In Vitro and In Vivo Detection of Mitophagy in Human Cells, C. Elegans, and Mice
Published on: November 22, 2017
Identification of Novel Vacuolin-1 Analogues as Autophagy Inhibitors by Virtual Drug Screening and Chemical Synthesis
Chang Chen1, Yingying Lu2,3, Ho Ming Siu4
1State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. c.chang@bjmu.edu.cn.
Abstract:
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.
Insights
Researchers identified novel chemical compounds that inhibit autophagy, a key cellular process implicated in diseases like cancer. These new autophagy inhibitors offer potential for developing more effective treatments.
Area of Science:
- Cell Biology
- Biochemistry
- Pharmacology
Background:
- Autophagy is a vital cellular degradation pathway crucial for maintaining homeostasis.
- Dysfunctional autophagy is linked to various human diseases, particularly cancer.
- Chemical modulators of autophagy are being investigated for therapeutic applications, especially in oncology.
Purpose of the Study:
- To identify novel autophagy inhibitors based on the vacuolin-1 scaffold.
- To explore the structure-activity relationship of vacuolin-1 analogues.
- To expand the repertoire of chemical tools for studying and targeting autophagy.
Main Methods:
- Virtual drug screening to identify potential vacuolin-1 analogues.
- Chemical synthesis of designed vacuolin-1 analogues.
- Experimental validation of autophagy inhibition by synthesized compounds.
Main Results:
- Virtual screening identified 14 potential autophagy inhibitors.
- 17 novel vacuolin-1 analogues were synthesized.
- 13 of the synthesized analogues demonstrated autophagy inhibitory activity.
- Several analogues exhibited potency comparable to vacuolin-1.
Conclusions:
- The study successfully expanded the range of available autophagy inhibitors.
- Key structural-activity relationships for vacuolin-1 analogues were elucidated.
- These findings provide a foundation for developing more potent vacuolin-1 derivatives and identifying their molecular targets.
