Research Papers:

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 and Liang Xu _

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Oncotarget. 2017; 8:51355-51369. https://doi.org/10.18632/oncotarget.17977

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Jia Yu1,2,*, Lan Lan2,*, Seth J. Lewin2, Steven A. Rogers3, Anuradha Roy4, Xiaoqing Wu2, Philip Gao5, John Karanicolas2,6, Jeffrey Aubé3,7, Baiwang Sun1 and Liang Xu2

1School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210089, China

2Department of Molecular Biosciences, The University of Kansas, Lawrence, Kansas 66045, USA

3Center of Biomedical Research Excellence, The University of Kansas, Lawrence, Kansas 66045, USA

4High Throughput Screening Laboratory, The University of Kansas, Lawrence, Kansas 66045, USA

5COBRE-PSF Protein Production Group, The University of Kansas, Lawrence, Kansas 66045, USA

6Center for Bioinformatics, The University of Kansas, Lawrence, Kansas 66045, USA

7Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, USA

*These authors contributed equally to this work

Correspondence to:

Liang Xu, email: [email protected]

Baiwang Sun, email: [email protected]

Keywords: Beclin 1 mimetics, autophagy, Bcl-xL protein, cancer, high-throughput screen

Received: March 26, 2017     Accepted: May 06, 2017     Published: May 18, 2017


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.

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