Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology, and Research), Singapore 138673.
Trends Biochem Sci. 2023 May;48(5):450-462. doi: 10.1016/j.tibs.2022.12.005. Epub 2023 Jan 26.
The Hippo signaling pathway inhibits the activity of the oncogenic YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif)-TEAD (TEA/ATTS domain) transcriptional complex. In cancers, inactivating mutations in upstream Hippo components and/or enhanced activity of YAP/TAZ and TEAD have been observed. The activity of this transcriptional complex can be effectively inhibited by targeting the TEAD family of transcription factors. The development of TEAD inhibitors has been driven by the discovery that TEAD has druggable hydrophobic pockets, and is currently at the clinical development stage. Three small molecule TEAD inhibitors are currently being tested in Phase I clinical trials. In this review, we highlight the role of TEADs in cancer, discuss various avenues through which TEAD activity can be inhibited, and outline the opportunities for the administration of TEAD inhibitors.
Hippo 信号通路抑制致癌 YAP（Yes 相关蛋白）/TAZ（与 PDZ 结合模体转录共激活因子）-TEAD（TEA/ATTS 结构域）转录复合物的活性。在癌症中，已观察到 Hippo 上游成分的失活突变和/或 YAP/TAZ 和 TEAD 的活性增强。通过靶向 TEAD 家族转录因子可以有效抑制该转录复合物的活性。小分子 TEAD 抑制剂的开发是基于发现 TEAD 具有可成药的疏水性口袋，目前处于临床开发阶段。目前正在进行 I 期临床试验以测试三种小分子 TEAD 抑制剂。在这篇综述中，我们强调了 TEAD 在癌症中的作用，讨论了抑制 TEAD 活性的各种途径，并概述了 TEAD 抑制剂给药的机会。
