• Zhisen Zhang, Zhaohu Lin, Zheng Zhou, Hong C Shen, S Frank Yan, Alexander V Mayweg, Zhiheng Xu, Ning Qin, Jason C Wong, Zhenshan Zhang, Yiping Rong, David C Fry, and Taishan Hu.
• Pharmaceutical Research and Early Development, Medicinal Chemistry, Discovery Technology, Molecular Design and Chemical Biology, Discovery Oncology, Roche Innovation Center Shanghai , Building 5, Lane 720, Cai Lun Road, Shanghai 201203, China ; Pharmaceutical Research and Early Development, Medicinal Chemistry, Discovery Technology, Molecular Design and Chemical Biology, Discovery Oncology, Roche Innovation Center Shanghai , Building 5, Lane 720, Cai Lun Road, Shanghai 201203, China.
• Acs Med Chem Lett. 2014 Sep 11; 5 (9): 993-8.

AbstractThe 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 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 YAP(50-171) (K d = 40 nM).

1 keywords...

hide…