Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors.
Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors.
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DOI：
10.1021/acs.jmedchem.2c01548
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发表时间：
2023-04-13
影响因子：
7.3
通讯作者：
Gray, Nathanael S.
中科院分区：
文献类型：
--
作者：
Lu, Wenchao;Fan, Mengyang;Ji, Wenzhi;Tse, Jason;You, Inchul;Ficarro, Scott B.;Tavares, Isidoro;Che, Jianwei;Kim, Audrey Y.;Zhu, Xijun;Boghossian, Andrew;Rees, Matthew G.;Ronan, Melissa M.;Roth, Jennifer A.;Hinshaw, Stephen M.;Nabet, Behnam;Corsello, Steven M.;Kwiatkowski, Nicholas;Marto, Jarrod A.;Zhang, Tinghu;Gray, Nathanael S.
转录增强关联域 (TEAD) 蛋白及其转录共激活子 yes 相关蛋白 (YAP) 和具有 PDZ 结合基序的转录共激活子 (TAZ) 是调节 Hippo 通路中基因表达的重要转录因子和辅助因子。在哺乳动物中，TEAD 家族有四个同源物：TEAD1 (TEF-1)、TEAD2 (TEF-4)、TEAD3 (TEF-5) 和 TEAD4 (TEF-3)。 TEAD/YAP 信号传导的异常表达和过度激活与多种恶性肿瘤有关。最近，TEAD 被认为在细胞中被棕榈酰化，并且亲脂性棕榈酸酯口袋已成功地被共价和非共价配体靶向。在本报告中，我们介绍了开发 MYF-03-176（化合物 22）作为选择性半胱氨酸共价 TEAD 抑制剂的药物化学工作。 MYF-03–176（化合物 22）显着抑制 TEAD 调节的基因表达和具有 TEAD 依赖性的细胞系的增殖，包括源自间皮瘤和脂肪肉瘤的细胞系。
Transcriptional enhanced associate domain (TEAD) proteins together with their transcriptional coactivator yes-associated protein (YAP) and transcriptional coactivator with the PDZ-binding motif (TAZ) are important transcription factors and cofactors that regulate gene expression in the Hippo pathway. In mammals, the TEAD families have four homologues: TEAD1 (TEF-1), TEAD2 (TEF-4), TEAD3 (TEF-5), and TEAD4 (TEF-3). Aberrant expression and hyperactivation of TEAD/YAP signaling have been implicated in a variety of malignancies. Recently, TEADs were recognized as being palmitoylated in cells, and the lipophilic palmitate pocket has been successfully targeted by both covalent and noncovalent ligands. In this report, we present the medicinal chemistry effort to develop MYF-03–176 (compound 22) as a selective, cysteine-covalent TEAD inhibitor. MYF-03–176 (compound 22) significantly inhibits TEAD-regulated gene expression and proliferation of the cell lines with TEAD dependence including those derived from mesothelioma and liposarcoma.
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