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Oncotarget. 2017 May 18;8(31):51355-51369. doi: 10.18632/oncotarget.17977. eCollection 2017 Aug 1.

Identification of novel small molecule Beclin 1 mimetics activating autophagy.

Author information

1
School of Chemistry and Chemical Engineering, Southeast University, Nanjing 210089, China.
2
Department of Molecular Biosciences, The University of Kansas, Lawrence, Kansas 66045, USA.
3
Center of Biomedical Research Excellence, The University of Kansas, Lawrence, Kansas 66045, USA.
4
High Throughput Screening Laboratory, The University of Kansas, Lawrence, Kansas 66045, USA.
5
COBRE-PSF Protein Production Group, The University of Kansas, Lawrence, Kansas 66045, USA.
6
Center for Bioinformatics, The University of Kansas, Lawrence, Kansas 66045, USA.
7
Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66045, USA.
#
Contributed equally

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.

KEYWORDS:

Bcl-xL protein; Beclin 1 mimetics; autophagy; cancer; high-throughput screen

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