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Identification of Quinolinols as Activators of TEAD-Dependent Transcription.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-12-02 , DOI: 10.1021/acschembio.9b00786 Ajaybabu V Pobbati 1 , Tom Mejuch 2 , Sayan Chakraborty 1 , Hacer Karatas 2 , Sakshibeedu R Bharath 1 , Stéphanie M Guéret 3, 4 , Pierre-Alexis Goy 1, 5 , Gernot Hahne 2 , Axel Pahl 2 , Sonja Sievers 2 , Ernesto Guccione 1 , Haiwei Song 1 , Herbert Waldmann 2, 6 , Wanjin Hong 1
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-12-02 , DOI: 10.1021/acschembio.9b00786 Ajaybabu V Pobbati 1 , Tom Mejuch 2 , Sayan Chakraborty 1 , Hacer Karatas 2 , Sakshibeedu R Bharath 1 , Stéphanie M Guéret 3, 4 , Pierre-Alexis Goy 1, 5 , Gernot Hahne 2 , Axel Pahl 2 , Sonja Sievers 2 , Ernesto Guccione 1 , Haiwei Song 1 , Herbert Waldmann 2, 6 , Wanjin Hong 1
Affiliation
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The transcriptional co-regulators YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif) are the vertebrate downstream effectors of the Hippo signaling pathway that controls various physiological and pathological processes. YAP and TAZ pair with the TEAD (TEA domain) family of transcription factors to initiate transcription. We previously identified a tractable pocket in TEADs, which has been physiologically shown to bind palmitate. Herein, a TEAD-palmitate interaction screen was developed to select small molecules occupying the palmitate-binding pocket (PBP) of TEADs. We show that quinolinols were TEAD-binding compounds that augment YAP/TAZ-TEAD activity, which was verified using TEAD reporter assay, RT-qPCR, and RNA-Seq analyses. Structure-activity relationship investigations uncovered the quinolinol substituents that are necessary for TEAD activation. We reveal a novel mechanism where quinolinols stabilize YAP/TAZ protein levels by occupying the PBP. The enhancement of YAP activity by quinolinols accelerates the in vivo wound closure in a mouse wound-healing model. Although small molecules that occupy the PBP have been shown to inhibit YAP/TAZ-TEAD activity, leveraging PBP to activate TEADs is a novel approach.
中文翻译：
喹啉醇作为TEAD依赖性转录激活剂的鉴定。
转录共调节因子YAP（Yes相关蛋白）和TAZ（具有PDZ结合基序的转录共激活因子）是控制各种生理和病理过程的河马信号通路的脊椎动物下游效应子。YAP和TAZ与TEAD（TEA域）家族的转录因子配对以启动转录。我们先前在TEADs中发现了一个易处理的口袋，从生理学角度来看，它可以与棕榈酸酯结合。本文中，开发了TEAD-棕榈酸酯相互作用筛选以选择占据TEAD的棕榈酸酯结合袋（PBP）的小分子。我们显示，喹啉醇是TEAD结合的化合物，可增加YAP / TAZ-TEAD活性，已通过TEAD报告基因分析，RT-qPCR和RNA-Seq分析进行了验证。结构-活性关系研究发现了TEAD激活所必需的喹啉醇取代基。我们揭示了一种新的机制，其中喹啉酚通过占据PBP来稳定YAP / TAZ蛋白水平。在小鼠伤口愈合模型中，喹啉醇提高了YAP活性，加速了体内伤口的闭合。尽管占据PBP的小分子已显示抑制YAP / TAZ-TEAD活性，但利用PBP激活TEAD是一种新颖的方法。
更新日期：2019-12-03
中文翻译：
喹啉醇作为TEAD依赖性转录激活剂的鉴定。
转录共调节因子YAP（Yes相关蛋白）和TAZ（具有PDZ结合基序的转录共激活因子）是控制各种生理和病理过程的河马信号通路的脊椎动物下游效应子。YAP和TAZ与TEAD（TEA域）家族的转录因子配对以启动转录。我们先前在TEADs中发现了一个易处理的口袋，从生理学角度来看，它可以与棕榈酸酯结合。本文中，开发了TEAD-棕榈酸酯相互作用筛选以选择占据TEAD的棕榈酸酯结合袋（PBP）的小分子。我们显示，喹啉醇是TEAD结合的化合物，可增加YAP / TAZ-TEAD活性，已通过TEAD报告基因分析，RT-qPCR和RNA-Seq分析进行了验证。结构-活性关系研究发现了TEAD激活所必需的喹啉醇取代基。我们揭示了一种新的机制，其中喹啉酚通过占据PBP来稳定YAP / TAZ蛋白水平。在小鼠伤口愈合模型中，喹啉醇提高了YAP活性，加速了体内伤口的闭合。尽管占据PBP的小分子已显示抑制YAP / TAZ-TEAD活性，但利用PBP激活TEAD是一种新颖的方法。
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