The Interdisciplinary Graduate Program in Integrative Biotechnology & Translational Medicine, Yonsei University, Incheon 21983, Republic of Korea.
Baobab AiBIO Co., Ltd., Incheon 21983, Republic of Korea.
J Med Chem. 2024 Nov 14;67(21):18957-18968. doi: 10.1021/acs.jmedchem.4c01393. Epub 2024 Nov 2.
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 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 , a covalent pan-TEAD inhibitor characterized by high potency and oral bioavailability.
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 Ctgf 和 Cyr61 等癌基因的转录上调。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 是使用基于结构的药物设计方法鉴定的，该方法利用了已知 TEAD 棕榈酰化位点抑制剂 K-975 的分子见解。对初始命中化合物的优化导致了化合物 的开发，这是一种共价泛 TEAD 抑制剂，具有高效力和口服生物利用度。
