journal article·2025-03Open access

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

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

Small· Volume 21· Issue 12

Abstract

Abstract 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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Research context

OpenAlex topics: Epigenetics and DNA Methylation · Cancer-related gene regulation · RNA modifications and cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macau Macao 999078 China

College of Food and Biological Engineering Jimei University Xiamen 361021 China

Key Laboratory of Tropical Biological Resources of Ministry of Education School of Pharmaceutical Sciences Hainan University Haikou 570228 China

Institute of Medical Research Northwestern Polytechnical University 127 West Youyi Road Xi'an Shaanxi 710072 China

Research & Development Institute of Northwestern Polytechnical University in Shenzhen 45 South Gaoxin Road Shenzhen 518057 China

Graduate Institute of Biomedical Engineering National Chung Hsing University Taichung 402 Taiwan

Department of Chemistry City University of Hong Kong Hong Kong 999077 China

The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE) School of Pharmacy Second Military Medical University (Naval Medical University) Shanghai 200433 China

Graduate Institute of Medicine College of Medicine Kaohsiung Medical University Kaohsiung 807 Taiwan

Department of Medical Laboratory Science and Biotechnology China Medical University Taichung City 404 Taiwan

Center of Applied Nanomedicine National Cheng Kung University Tainan 701 Taiwan

Funding

National Natural Science Foundation of China · National Key Research and Development Program of China · Fundamental Research Funds for the Central Universities · Basic and Applied Basic Research Foundation of Guangdong Province

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