The Hippo pathway controls in organ size and tissue homeostasis through regulating cell growth, proliferation and apoptosis. Phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) regulates their nuclear import and therefore their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several solid cancers making YAP/TAZ-TEAD interaction a new anti-cancer target. We identified by screening a small in-house library, 5-benzyloxindole which binds to hTEAD2 at its internal/palmitate pocket. Its optimization led to covalent inhibitors bearing different warhead. Soaking with hTEAD2 gave seven new crystal structures where the ligands occupied palmitate pocket. 5-Benzyloxyindoles armed with vinylsulfamide moiety inhibit YAP/TAZ-TEAD target genes expression and breast cancer cell proliferation at micromolar concentration.

中文翻译：

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面向内部口袋 TEAD C 端结构域的配体设计


Hippo 通路通过调节细胞生长、增殖和细胞凋亡来控制器官大小和组织稳态。转录共激活因子 YAP （Yes 相关蛋白） 和 TAZ （具有 PDZ 结合基序的转录共激活因子） 的磷酸化调节它们的核输入，从而调节它们与 TEAD （转录增强相关结构域） 的相互作用。YAP、TAZ 和 TEAD 在几种实体癌中失调，使 YAP/TAZ-TEAD 相互作用成为新的抗癌靶点。我们通过筛选一个小型的内部文库 5-苄氧吲哚来确定，该文库在其内部/棕榈酸酯口袋与 hTEAD2 结合。它的优化导致带有不同弹头的共价抑制剂。用 hTEAD2 浸泡得到 7 种新的晶体结构，其中配体占据棕榈酸酯口袋。5-苄基氧吲哚与乙烯基磺酰胺部分武装，在微摩尔浓度下抑制 YAP/TAZ-TEAD 靶基因表达和乳腺癌细胞增殖。