The Hippo pathway is involved in organ size control and tissue homeostasis by regulating cell growth, proliferation and apoptosis. It controls the phosphorylation of the transcription co-activator YAP (Yes associated protein) and TAZ (Transcriptional coactivator with PDZ-binding motif) in order to control their nuclear import and their interaction with TEAD (Transcriptional Enhanced Associated Domain). YAP, TAZ and TEADs are dysregulated in several cancers making YAP/TAZ-TEAD interaction a new emerging anti-cancer target. We report the synthesis of a set of trisubstituted pyrazoles which bind to hTEAD2 at the interface 2 revealing for the first time a cryptic pocket created by the movement of the phenol ring of Y382. Compound 6 disrupts YAP/TAZ-TEAD interaction in HEK293T cells and inhibits TEAD target genes and cell proliferation in MDA-MB-231 cells. Compound 6 is therefore the first inhibitor of YAP/TAZ-TEAD targeting interface 2. This molecule could serve with other pan-TEAD inhibitors such as interface 3 ligands, for the delineation of the relative importance of VGLL vs YAP/TAZ in a given cellular model.

Hippo通路通过调节细胞生长、增殖和凋亡参与器官大小控制和组织稳态。它控制转录共激活因子 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，以控制它们的核输入以及它们与 TEAD（转录增强相关域）的相互作用。YAP、TAZ 和 TEAD 在几种癌症中失调，使 YAP/TAZ-TEAD 相互作用成为新兴的抗癌靶点。我们报告了一组三取代吡唑的合成，它们在界面 2 处与 hTEAD2 结合，首次揭示了由 Y382 的苯酚环运动产生的神秘口袋。化合物6破坏 HEK293T 细胞中的 YAP/TAZ-TEAD 相互作用并抑制 MDA-MB-231 细胞中的 TEAD 靶基因和细胞增殖。因此，化合物6是 YAP/TAZ-TEAD 靶向界面 2 的第一个抑制剂。该分子可与其他泛 TEAD 抑制剂如界面 3 配体一起使用，以描述 VGLL与YAP/TAZ 在给定细胞中的相对重要性模型。