A covalent inhibitor of the YAP-TEAD transcriptional complex identified by high-throughput screening.
A covalent inhibitor of the YAP-TEAD transcriptional complex identified by high-throughput screening.
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高通量筛选鉴定的YAP-tead转录复合体的共价抑制物。
DOI：
10.1039/d3cb00044c
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发表时间：
2023-11-01
影响因子：
4.1
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中科院分区：
文献类型：
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yes相关蛋白（YAP）是Hippo通路下游的主要转录效应因子，调节动物必需的细胞生长和再生过程。然而，在癌症中观察到的YAP的激活驱动细胞增殖，转移，化疗耐药和免疫抑制，使其成为开发肿瘤精准治疗的关键兴趣。因此，通过靶向其重要的协同调节因子，TEA结构域转录因子（TEADs）对YAP进行药理学抑制可能会促进敏感肿瘤类型的肿瘤清除。基于荧光偏振的高通量筛选超过80万个不同的小分子，在这里，我们报告了一种基于吡唑并嘧啶的支架，它可以抑制YAP和TEADs的结合。基于药物化学的优化鉴定出mCMY020，这是一种有效的TEAD转录活性共价抑制剂，它占据了TEAD上一个保守的中心棕榈酰化位点。一种基于吡唑嘧啶的抑制剂共价靶向四种TEAD类似物，抑制依赖YAP的细胞生长和转录。
Yes-associated protein (YAP), the master transcriptional effector downstream of the Hippo pathway, regulates essential cell growth and regenerative processes in animals. However, the activation of YAP observed in cancers drives cellular proliferation, metastasis, chemoresistance, and immune suppression, making it of key interest in developing precision therapeutics for oncology. As such, pharmacological inhibition of YAP by targeting its essential co-regulators, TEA domain transcription factors (TEADs) would likely promote tumor clearance in sensitive tumor types. From a fluorescence polarization-based high throughput screen of over 800 000 diverse small molecules, here we report the identification of a pyrazolopyrimidine-based scaffold that inhibits association of YAP and TEADs. Medicinal chemistry-based optimization identified mCMY020, a potent, covalent inhibitor of TEAD transcriptional activity that occupies a conserved, central palmitoylation site on TEADs. A pyrazolopyrimidine-based inhibitor covalently targets the four TEAD paralogs, inhibiting YAP dependent cell growth and transcription.