School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023 Jiangsu, China.
Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 210203, China.
J Med Chem. 2021 Jun 24;64(12):8194-8207. doi: 10.1021/acs.jmedchem.0c02261. Epub 2021 Jun 2.
Disruption of EZH2-embryonic ectoderm development (EED) protein-protein interaction (PPI) is a new promising cancer therapeutic strategy. We have previously reported the discovery of astemizole, a small-molecule inhibitor targeting the EZH2-EED PPI. Herein, we report the cocrystal structure of EED in complex with astemizole at 2.15 Å. The structure elucidates the detailed binding mode of astemizole to EED and provides a structure-guided design for the discovery of a novel EZH2-EED interaction inhibitor, DC-PRC2in-01, with an affinity of 4.56 μM. DC-PRC2in-01 destabilizes the PRC2 complex, thereby leading to the degradation of PRC2 core proteins and the decrease of global H3K27me3 levels in cancer cells. The proliferation of PRC2-driven lymphomas cells is effectively inhibited, and the cell cycle is arrested in the G0/G1 phase. Together, these data demonstrate that DC-PRC2in-01 could be an effective chemical probe for investigating the PRC2-related physiology and pathology and providing a promising chemical scaffold for further development.
破坏 EZH2-胚胎外胚层发育（EED）蛋白-蛋白相互作用（PPI）是一种新的有前途的癌症治疗策略。我们之前曾报道过发现阿司咪唑，一种针对 EZH2-EED PPI 的小分子抑制剂。在此，我们报告了 EED 与阿司咪唑复合物的 2.15 Å 共晶结构。该结构阐明了阿司咪唑与 EED 的详细结合模式，并为发现新型 EZH2-EED 相互作用抑制剂 DC-PRC2in-01 提供了结构指导，其亲和力为 4.56 μM。DC-PRC2in-01 使 PRC2 复合物不稳定，从而导致 PRC2 核心蛋白降解和癌细胞中全局 H3K27me3 水平降低。PRC2 驱动的淋巴瘤细胞的增殖被有效抑制，细胞周期被阻滞在 G0/G1 期。总之，这些数据表明，DC-PRC2in-01 可以作为研究 PRC2 相关生理学和病理学的有效化学探针，并为进一步开发提供有前途的化学支架。
