In the Hippo signaling pathway, the palmitoylated transcriptional enhanced associated domain (TEAD) protein interacts with the coactivator Yes-associated protein/PDZ-binding motif, leading to transcriptional upregulation of oncogenes such as Ctgf and Cyr61. Consequently, targeting the palmitoylation sites of TEAD has emerged as a promising strategy for treating TEAD-dependent cancers. Compound 1 was identified using a structure-based drug design approach, leveraging the molecular insights gained from the known TEAD palmitoylation site inhibitor, K-975. Optimization of the initial hit compound resulted in the development of compound 3, a covalent pan-TEAD inhibitor characterized by high potency and oral bioavailability.

中文翻译：

---

泛转录增强相关结构域棕榈酰化口袋共价抑制剂


在 Hippo 信号通路中，棕榈酰化转录增强相关结构域 （TEAD） 蛋白与共激活因子 Yes 相关蛋白/PDZ 结合基序相互作用，导致癌基因（如 Ctgf 和 Cyr61）的转录上调。因此，靶向 TEAD 的棕榈酰化位点已成为治疗 TEAD 依赖性癌症的一种有前途的策略。化合物 1 是使用基于结构的药物设计方法鉴定的，利用从已知的 TEAD 棕榈酰化位点抑制剂 K-975 获得的分子见解。对初始苗头化合物的优化导致了化合物 3 的开发，这是一种共价 pan-TEAD 抑制剂，具有高效力和口服生物利用度。