Identification of novel small molecule Beclin 1 mimetics activating autophagy

Jia Yu, Lan Lan, Seth J. Lewin, Steven A. Rogers, Anuradha Roy, Xiaoqing Wu, Philip Gao, John Karanicolas, Jeffrey Aubé, Baiwang Sun, Liang Xu

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

Anti-apoptotic proteins Bcl-2 and Bcl-xL could block autophagy by binding to Beclin 1 protein, an essential inducer of autophagy. Compounds mimicking Beclin 1 might be able to disrupt Bcl-xL/2-Beclin 1 interaction, free out Beclin 1, and thus trigger autophagy. In order to identify small molecule Beclin 1 mimetics, a fluorescence polarization-based high-throughput screening of 50,316 compounds was carried out with a Z' score of 0.82 ± 0.05, and an outcome of 58 hits. After the structure analysis, three acridine analogues were unveiled and confirmed using the fluorescence polarization assay and the surface plasmon resonance assay. Moreover, a set of 17 additional acridine analogues was prepared and tested. Compound 7 showed selectivity for Bcl-xL (KD = 6.5 μM) over Bcl-2 (KD = 160 μM) protein, and potent cytotoxicity (nanomolar scale) in PC-3, PC-3a and DU145 prostate cancer cells. Furthermore, induction of autophagy was also demonstrated in PC-3 and PC-3a cells treated with some acridine compounds by LC3 conversion immunoblotting and LC3 fluorescence microscopy. These Beclin 1 mimetics will be invaluable tools for developing novel autophagy inducers, better understanding the roles of autophagy in cancer, and will contribute to cancer therapy.

Original languageEnglish
Pages (from-to)51355-51369
Number of pages15
JournalOncotarget
Volume8
Issue number31
DOIs
StatePublished - Feb 7 2017

Keywords

  • Autophagy
  • Bcl-xL protein
  • Beclin 1 mimetics
  • Cancer
  • High-throughput screen

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