Design, Synthesis, and Biological Evaluation of a Potent Dual EZH2–BRD4 Inhibitor for the Treatment of Some Solid Tumors

• Published in: Journal of medicinal chemistry 2023-02, Vol.66 (4), p.2646-2662
• Main Authors: Huang, Niannian, Liao, Ping, Zuo, Yunxia, Zhang, Lidan, Jiang, Ruotian
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Cycle Proteins - antagonists & inhibitors; Cell Line, Tumor; Drug Design; Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Histones - metabolism; Humans; Mice; Neoplasms - drug therapy; Nuclear Proteins - metabolism; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01607

Enhancer of zeste homolog 2 (EZH2) mediates the trimethylation of histone 3 lysine 27 (H3K27) to promote gene silencing. Inhibition of EZH2 is a viable strategy for cancer treatment; however, only a small subset of hematological malignancies are sensitive to small-molecule EZH2 inhibitors. EZH2 inhibitors cause H3K27 acetylation in most solid tumors, leading to drug resistance. Bromodomain-containing protein 4 (BRD4) inhibitors were reported to enhance the sensitivity of solid tumors to EZH2 inhibitors. Thus, we designed and evaluated a series of dual EZH2–BRD4 inhibitors. ZLD-2, the most promising compound, exhibited potent inhibitory activity against EZH2 and BRD4. Compared to the EZH2 inhibitor GSK126, ZLD-2 displayed potent antiproliferation activity against breast, lung, bladder, and pancreatic cancer cells. In vivo, ZLD-2 exhibited antitumor activity in a BxPC-3 mouse xenograft model, whereas GSK126 promoted tumor growth. Thus, ZLD-2 may be a lead compound for treating solid tumors.