Journal of medicinal chemistry · 2023
Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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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
Аннотация
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.