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Identification of Novel Vacuolin-1 Analogues as Autophagy Inhibitors by Virtual Drug Screening and Chemical Synthesis.
Chen, Chang; Lu, Yingying; Siu, Ho Ming; Guan, Jintao; Zhu, LongChao; Zhang, Shuang; Yue, Jianbo; Zhang, Liangren.
Afiliación
  • Chen C; State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. c.chang@bjmu.edu.cn.
  • Lu Y; City University of Hong Kong Shen Zhen Research Institute, Shenzhen 518057, China. superchristie@sina.com.
  • Siu HM; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China. superchristie@sina.com.
  • Guan J; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China. hmsiu9-c@my.cityu.edu.hk.
  • Zhu L; City University of Hong Kong Shen Zhen Research Institute, Shenzhen 518057, China. kam.guan@hotmail.com.
  • Zhang S; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China. kam.guan@hotmail.com.
  • Yue J; City University of Hong Kong Shen Zhen Research Institute, Shenzhen 518057, China. longchao.zhu@outlook.com.
  • Zhang L; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China. longchao.zhu@outlook.com.
Molecules ; 22(6)2017 May 27.
Article en En | MEDLINE | ID: mdl-28555021
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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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Autofagia / Evaluación Preclínica de Medicamentos / Compuestos Heterocíclicos de 4 o más Anillos Tipo de estudio: Diagnostic_studies / Screening_studies Idioma: En Revista: Molecules Año: 2017 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Autofagia / Evaluación Preclínica de Medicamentos / Compuestos Heterocíclicos de 4 o más Anillos Tipo de estudio: Diagnostic_studies / Screening_studies Idioma: En Revista: Molecules Año: 2017 Tipo del documento: Article País de afiliación: China