Structure-Based Design and Synthesis of Potent Cyclic Peptides Inhibiting the YAP–TEAD Protein–Protein Interaction

The YAP–TEAD protein–protein interaction (PPI) mediates the oncogenic function of YAP, and inhibitors of this PPI have potential usage in treatment of YAP-involved cancers. Here we report the design and synthesis of potent cyclic peptide inhibitors of the YAP–TEAD interaction. A truncation study of YAP interface 3 peptide identified YAP^84–100 as a weak peptide inhibitor (IC₅₀ = 37 μM), and an alanine scan revealed a beneficial mutation, D94A. Subsequent replacement of a native cation−π interaction with an optimized disulfide bridge for conformational constraint and synergistic effect between macrocyclization and modification at positions 91 and 93 greatly boosted inhibitory activity. Peptide <b>17</b> was identified with an IC₅₀ of 25 nM, and the binding affinity (<i>K</i>_d = 15 nM) of this 17mer peptide to TEAD1 proved to be stronger than YAP^50–171 (<i>K</i>_d = 40 nM)