作者
Timo Heinrich,Dániel 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 L. Carswell,Heike Schilke,Patrizia Diehl,Benjamin Doerfel,Djordje Müsil,Elisabeth Trivier,Rebecca Broome,Stephen Marshall,Alexander Balsiger,Erik Friedrich,Ana R. Lemos,Sandra P. Santos,Pedro M. F. Sousa,Filipe Freire,Tiago M. Bandeiras,Alessio Bortoluzzi,Dirk Wienke
摘要
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.