Details

Autor(en) / Beteiligte

• Zhang, Zhisen
• Lin, Zhaohu
• Zhou, Zheng
• Shen, Hong C
• Yan, S. Frank
• Mayweg, Alexander V
• Xu, Zhiheng
• Qin, Ning
• Wong, Jason C
• Zhang, Zhenshan
• Rong, Yiping
• Fry, David C
• Hu, Taishan

Titel

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

Ist Teil von

• ACS medicinal chemistry letters, 2014-09, Vol.5 (9), p.993-998

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2014

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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 YAP84–100 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 17 was identified with an IC50 of 25 nM, and the binding affinity (K d = 15 nM) of this 17mer peptide to TEAD1 proved to be stronger than YAP50–171 (K d = 40 nM).