Taking the structural information into account, we were able to tune the TEAD selectivity for a specific chemotype. However, different TEAD selectivity profiles did not affect the compound potency or efficacy in the NCI-H226 viability assay. Amides based on MSC-4106 or analogues showed improved viability efficacy compared with the corresponding acids. The amide M3686 exhibited AUC-driven efficacy in NCI-H226 xenograft models and had an improved 25-fold lower human dose prediction than MSC-4106. MSC-4106 was also used in HDX-MS studies to aid in the understanding of the MoA of P-site binding TEAD inhibitors. Artificial P-site binders rigidify certain areas in the periphery of the transcription factor that seem to be crucial for cofactor interaction, whereas a native fatty acid increased the protein dynamics of cofactor-binding interfaces.

中文翻译：

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TEAD P 位点结合配体 MSC-4106 的 MoA 研究及其对 TEAD1 选择性酰胺 M3686 的优化


考虑到结构信息，我们能够调整特定化学型的 TEAD 选择性。然而，不同的 TEAD 选择性特征不会影响 NCI-H226 活力测定中的化合物效力或功效。与相应的酸相比，基于 MSC-4106 或类似物的酰胺显示出更高的活力功效。酰胺 M3686 在 NCI-H226 异种移植模型中表现出 AUC 驱动的疗效，并且比 MSC-4106 的人类剂量预测低 25 倍。MSC-4106 还用于 HDX-MS 研究，以帮助了解 P 位点结合 TEAD 抑制剂的 MoA。人工 P 位点结合剂使转录因子外围的某些区域刚性化，这些区域似乎对辅因子相互作用至关重要，而天然脂肪酸增加了辅因子结合界面的蛋白质动力学。