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

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2024-12-20 DOI:10.1021/acs.jmedchem.4c01949

Timo Heinrich, Daniel Schwarz, Carl Petersson, Jakub Gunera, Sakshi Garg, Richard Schneider, Marina Keil, Lisa Grimmeisen, Andrea Unzue Lopez, Lisa Albers, Sarah Schlesiger, Alessia Gambardella, Joerg Bomke, Emma Carswell, Heike Schilke, Patrizia Diehl, Benjamin Doerfel, Djordje Musil, Elisabeth Trivier, Rebecca Broome, Sam Marshall, Alexander Balsiger, Erik Friedrich, Ana R. Lemos, Sandra P. Santos, Pedro M. F. Sousa, Filipe Freire, Tiago M. Bandeiras, Alessio Bortoluzzi, Dirk Wienke

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引用次数: 0

摘要

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选择性谱在NCI-H226活力试验中不影响化合物的效力或功效。与相应的酸相比，基于MSC-4106或类似物的酰胺具有更高的活力效率。酰胺M3686在NCI-H226异种移植物模型中表现出auc驱动的功效，并且比MSC-4106的人剂量预测低25倍。MSC-4106也用于HDX-MS研究，以帮助了解p位点结合TEAD抑制剂的MoA。人工p位点结合物使转录因子外围的某些区域变得僵硬，而这些区域似乎对辅因子相互作用至关重要，而天然脂肪酸则增加了辅因子结合界面的蛋白质动力学。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

MoA Studies of the TEAD P-Site Binding Ligand MSC-4106 and Its Optimization to TEAD1-Selective Amide M3686

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MoA Studies of the TEAD P-Site Binding Ligand MSC-4106 and Its Optimization to TEAD1-Selective Amide M3686

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.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.