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Identification of novel small molecule Beclin 1 mimetics activating autophagy
Yu, Jia Lan, Lan Lewin, Seth J. Rogers, Steven A. Roy, Anuradha Wu, Xiaoqing Gao, Philip Karanicolas, John Aubé, Jeffrey Sun, Baiwang
Yu, Jia
Lan, Lan
Lewin, Seth J.
Rogers, Steven A.
Roy, Anuradha
Wu, Xiaoqing
Gao, Philip
Karanicolas, John
Aubé, Jeffrey
Sun, Baiwang
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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.
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2017-05-18
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Keywords
Beclin 1 mimetics, Autophagy, Bcl-xL protein, Cancer, High-throughput screen
Citation
Yu, Jia et al. “Identification of novel small molecule Beclin 1 mimetics activating autophagy” Oncotarget vol. 8,31 51355-51369. 18 May. 2017, doi:10.18632/oncotarget.17977