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Structure-Guided Development of Small-Molecule PRC2 Inhibitors Targeting EZH2-EED Interaction
Daohai Du1,2, Dandan Xu3,4, Licheng Zhu5,6,7
1School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023 Jiangsu, China.
Journal of Medicinal Chemistry
|June 2, 2021
Summary
Researchers developed a new inhibitor, DC-PRC2in-01, targeting the EZH2-embryonic ectoderm development (EED) protein-protein interaction crucial in cancer. This compound effectively inhibits cancer cell proliferation and offers a promising scaffold for future drug development.
Area of Science:
- Oncology
- Structural Biology
- Chemical Biology
Background:
- Targeting protein-protein interactions (PPIs) like EZH2-EED is a novel cancer therapy strategy.
- Astemizole was previously identified as a small-molecule inhibitor of the EZH2-EED PPI.
Purpose of the Study:
- To determine the cocrystal structure of EED with astemizole.
- To design and characterize a novel inhibitor of the EZH2-EED interaction based on structural insights.
- To evaluate the efficacy of the novel inhibitor in cancer cells.
Main Methods:
- Cocrystallography to determine the EED-astemizole complex structure at 2.15 Å resolution.
- Structure-guided drug design to develop a new inhibitor, DC-PRC2in-01.
- Biochemical assays to measure binding affinity (Kd = 4.56 μM).
- Cell-based assays to assess PRC2 complex stability, H3K27me3 levels, cell proliferation, and cell cycle arrest.
Main Results:
- The cocrystal structure revealed the binding mode of astemizole to EED.
- A novel inhibitor, DC-PRC2in-01, was designed with a Kd of 4.56 μM.
- DC-PRC2in-01 destabilized the PRC2 complex, reduced H3K27me3 levels, inhibited proliferation of lymphoma cells, and induced G0/G1 cell cycle arrest.
Conclusions:
- DC-PRC2in-01 is a potent inhibitor of the EZH2-EED interaction.
- The compound effectively targets PRC2-driven cancers by destabilizing the PRC2 complex.
- DC-PRC2in-01 serves as a valuable chemical probe and a promising scaffold for developing new cancer therapeutics.
