期刊
ACTA PHARMACOLOGICA SINICA
卷 39, 期 2, 页码 302-310出版社
ACTA PHARMACOLOGICA SINICA
DOI: 10.1038/aps.2017.59
关键词
PRC2; EZH2; EED; protein-protein interaction; fluorescence polarization; high-throughput screening; apomorphine hydrochloride; oxyphenbutazone; nifedipine; ergonovine maleate
资金
- Ministry of Science and Technology of China [2015CB910304]
- National Natural Science Foundation of China [21472208, 81625022, 21210003, 81230076, 91313000]
- State Key Laboratory of Toxicology and Medical Countermeasures, Academy of Military Medical Science [TMC201505]
Aberrant activity of enhancer of zeste homolog 2 (EZH2) is associated with a wide range of human cancers. The interaction of EZH2 with embryonic ectoderm development (EED) is required for EZH2's catalytic activity. Inhibition of the EZH2-EED complex thus represents a novel strategy for interfering with the oncogenic potentials of EZH2 by targeting both its catalytic and non-catalytic functions. To date, there have been no reported high-throughput screening (HTS) assays for inhibitors acting at the EZH2-EED interface. In this study, we developed a fluorescence polarization (FP)-based HTS system for the discovery of EZH2-EED interaction inhibitors. The tracer peptide sequences, positions of fluorescein labeling, and a variety of physicochemical conditions were optimized. The high Z' factors (>0.9) at a variety of DMSO concentrations suggested that this system is robust and suitable for HTS. The minimal sequence requirement for the EZH2-EED interaction was determined by using this system. A pilot screening of an in-house compound library containing 1600 FDA-approved drugs identified four compounds (apomorphine hydrochloride, oxyphenbutazone, nifedipine and ergonovine maleate) as potential EZH2-EED interaction inhibitors.
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