A Bioactive Benzimidazole-Cyclometalated Iridium(III) Complex as an Epigenetic Regulator through Effectively Interrupting the EED-EZH2 Interaction.

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Tác giả: Daniel Shiu-Hin Chan, Shasha Cheng, Shaozhen Jing, Yi-Xuan Lan, Chung-Hang Leung, Jian Li, Chunquan Sheng, Ying-Qi Song, Hui-Min David Wang, Ling Wang, Wanhe Wang, Chun-Yuen Wong

Ngôn ngữ: eng

Ký hiệu phân loại: 594.38 *Pulmonata

Thông tin xuất bản: Germany : Small (Weinheim an der Bergstrasse, Germany) , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 208931

Epigenetic regulation plays a fundamental role in controlling gene expression and maintaining cellular identity. Among epigenetic processes, the translocation of methyltransferases is critical for the modification of chromatin structure and transcriptional activity. The regulation of these translocation events and the mechanisms involved are complex, yet critical for understanding and manipulating epigenetic states. Therefore, novel strategies are required for detecting and visualizing the movement and interaction of methyltransferases within cells. Using enhancer of zeste homolog 2 (EZH2) methyltransferase as an example, a bifunctional compound capable of both monitoring and disrupting its translocation process is developed by targeting the protein-protein interaction (PPI) between embryonic ectoderm development (EED) and EZH2. The Ir(III) complex 1 bound enthalpically to EED and effectively inhibited the methyltransferase activity of EZH2. Moreover, disruption of the EED-EZH2 PPI led to increased transcriptional activity of P21 and P27, resulting in the suppression of triple-negative breast cancer (TNBC) cell proliferation. Excitingly, 1 suppressed tumor metastasis in a TNBC mouse model in vivo. To our knowledge, complex 1 is the first metal-based bifunctional therapeutic agent designed to probe and inhibit the EED-EZH2 PPI, highlighting the feasibility and significance of using metal complexes to monitor and influence methyltransferase translocations for therapeutic applications.
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