Discovery of a cryptic site at the interface 2 of TEAD - Towards a new family of YAP/TAZ-TEAD inhibitors
Discovery of a cryptic site at the interface 2 of TEAD - Towards a new family of YAP/TAZ-TEAD inhibitors
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DOI：
10.1016/j.ejmech.2021.113835
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发表时间：
2021-09-10
影响因子：
6.7
通讯作者：
Cotelle, Philippe
中科院分区：
文献类型：
--
作者：
Sturbaut, Manon;Bailly, Fabrice;Cotelle, Philippe
Hippo 通路通过调节细胞生长、增殖和凋亡来参与器官大小控制和组织稳态。它控制转录辅激活因子 YAP（Yes 相关蛋白）和 TAZ（具有 PDZ 结合基序的转录辅激活因子）的磷酸化，以控制它们的核输入及其与 TEAD（转录增强相关域）的相互作用。 YAP、TAZ 和 TEAD 在多种癌症中失调，使得 YAP/TAZ-TEAD 相互作用成为新的抗癌靶点。我们报道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 Y382 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。该分子可以与其他泛 TEAD 抑制剂（例如界面 3 配体）一起使用，用于描述给定细胞模型中 VGLL 与 YAP/TAZ 的相对重要性。 (C) 2021 Elsevier Masson SAS。版权所有。
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. (C) 2021 Elsevier Masson SAS. All rights reserved.