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

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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Abstract

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.