Heinrich Timo, Schwarz Daniel, Petersson Carl, Gunera Jakub, Garg Sakshi, Schneider Richard, Keil Marina, Grimmeisen Lisa, Unzue Lopez Andrea, Albers Lisa, Schlesiger Sarah, Gambardella Alessia, Bomke Joerg, Carswell Emma, Schilke Heike, Diehl Patrizia, Doerfel Benjamin, Musil Djordje, Trivier Elisabeth, Broome Rebecca, Marshall Sam, Balsiger Alexander, Friedrich Erik, Lemos Ana R, Santos Sandra P, Sousa Pedro M F, Freire Filipe, Bandeiras Tiago M, Bortoluzzi Alessio, Wienke Dirk
Merck Healthcare KGaA, Frankfurter Str. 250, 64293 Darmstadt, Germany.
Cancer Research Horizons, Jonas Webb Building, Babraham Research Campus, CambridgeCB22 3AT, U.K.
J Med Chem. 2025 Mar 27;68(6):6149-6164. doi: 10.1021/acs.jmedchem.4c01949. Epub 2024 Dec 20.
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 or analogues showed improved viability efficacy compared with the corresponding acids. The amide exhibited AUC-driven efficacy in NCI-H226 xenograft models and had an improved 25-fold lower human dose prediction than . 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.
考虑到结构信息，我们能够调整TEAD对特定化学类型的选择性。然而，不同的TEAD选择性概况并未影响化合物在NCI-H226活力测定中的效力或功效。与相应的酸相比，基于[具体物质]或其类似物的酰胺显示出改善的活力功效。酰胺[具体物质]在NCI-H226异种移植模型中表现出AUC驱动的功效，并且与[另一物质]相比，其预测的人体剂量降低了25倍。[具体物质]还用于氢/氘交换质谱（HDX-MS）研究，以帮助理解P位点结合TEAD抑制剂的作用机制。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。
