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.