Transcriptional enhancer associated domain family members (TEADs) are the most important downstream effectors that play the pivotal role in the development, regeneration and tissue homeostasis. Recent biochemical studies have demonstrated that TEADs could undergo autopalmitoylation that is indispensable for its function making the lipid-binding pocket an attractive target for chemical intervention. Herein, through structure-based virtual screen and rational medicinal chemistry optimization, we identified DC-TEADin02 as the most potent, selective, covalent TEAD autopalmitoylation inhibitor with the IC50 value of 197 ± 19 nM while it showed minimal effect on TEAD-YAP interaction. Further biochemical counter-screens demonstrate the specific thiol reactivity and selectivity of DC-TEADin02 over the kinase family, lipid-binding proteins and epigenetic targets. Notably, DC-TEADin02 inhibited TEADs transcription activity leading to downregulation of YAP-related downstream gene expression. Taken together, our findings proved the validity of modulating transcriptional output in the Hippo signaling pathway through irreversible chemical interventions of TEADs autopalmitoylation activity, which may serve as a qualified chemical tool for TEADs palmitoylation-related studies in the future.

中文翻译：

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乙烯基磺酰胺衍生物作为高效，共价TEAD自棕榈酸酯化抑制剂的发现和生物学评估。

转录增强子相关域家族成员（TEADs）是最重要的下游效应子，在发育，再生和组织稳态中发挥关键作用。最近的生化研究表明，TEADs可能会经历自身的棕榈酰化作用，这对其功能是必不可少的，这使得脂质结合袋成为化学干预的有吸引力的靶标。在本文中，通过基于结构的虚拟筛选和合理的药物化学优化，我们确定DC-TEADin02是最有效，选择性最高的共价TEAD自戊二酰化抑制剂，IC50值为197±19 nM，而对TEAD-YAP相互作用的影响却最小。进一步的生化反筛查证明了DC-TEADin02在激酶家族中的特异性硫醇反应性和选择性，脂质结合蛋白和表观遗传学靶标。值得注意的是，DC-TEADin02抑制TEADs转录活性，从而导致YAP相关下游基因表达的下调。综上所述，我们的发现证明了通过不可逆的TEADs自身棕榈酰化活性的化学干预，在Hippo信号通路中调节转录输出的有效性，这可能会在将来成为TEAD棕榈酰化相关研究的合格化学工具。