TOWARDS THE DESIGN OF LIGANDS OF THE INTERNAL POCKET TEADS C-TERMINAL DOMAIN

IF 6 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2024-11-12 DOI:10.1016/j.ejmech.2024.117026

Florine TOULOTTE, Mathilde COEVOET, Maxime LIBERELLE, Fabrice BAILLY, Benjamin ZAGIEL, Muriel GELIN, Frédéric ALLEMAND, Patrick FOURQUET, Patricia MELNYK, G.U.I.C.H.O.U. Jean-François, Philippe COTELLE

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Abstract

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.

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设计内袋 Teads c-terminal 结构域的配体

希波通路通过调节细胞生长、增殖和凋亡来控制器官大小和组织稳态。转录辅激活因子 YAP（是相关蛋白）和 TAZ（具有 PDZ 结合基调的转录辅激活因子）的磷酸化调节它们的核输入，从而调节它们与 TEAD（转录增强相关域）的相互作用。YAP、TAZ和TEAD在几种实体瘤中失调，使得YAP/TAZ-TEAD相互作用成为新的抗癌靶点。我们通过筛选内部小型文库发现了 5-苄基吲哚，它能在 hTEAD2 的内部/棕榈酸酯口袋与之结合。对其进行优化后，我们得到了带有不同弹头的共价抑制剂。通过与 hTEAD2 的浸泡，得到了配体占据棕榈酸酯袋的七个新晶体结构。含有乙烯基硫酰胺分子的 5-苄氧基吲哚能在微摩尔浓度下抑制 YAP/TAZ-TEAD 靶基因的表达和乳腺癌细胞的增殖。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.