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

Abstract

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 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).

Peptide 17, an inhibitor of YAP/TEAD4 pathway, mitigates lung cancer malignancy

“…Several molecules have shown inhibitory effects on YAP. siRNAs have been designed to inhibit YAP activity [23], and YAP-like peptides without biological activity have been developed that show priority in combination with TEAD [14,24]. Other YAP inhibitors, for example statin, with restricted efficiency have also been applied to decrease lung cancer cell YAP expression [25].…”

“…Mechanistically, when the Hippo pathway is inactivated, YAP interacts with transcriptional enhancer activation domain (TEAD) family members to promote cellular proliferation and inhibit apoptosis [11,12]. Given the critical role of YAP in lung cancer, peptide 17, a promising inhibitor of YAP/TEAD4 signaling, was supposed to ameliorate the malignancy of lung cancer [13,14].…”

YAP-1 Promotes Tregs Differentiation in Hepatocellular Carcinoma by Enhancing TGFBR2 Transcription

“…Overexpression of YAP-1 in T cells can significantly increase the Treg percentage while knockdown of YAP-1 expression decreased the Treg percentage significantly. Also reduce the activation of YAP-1 by using its inhibitor peptide 17 [21] can significantly reduce the percentage of Tregs (Fig. 3B).…”

The Hippo effector YAP regulates the response of cancer cells to MAPK pathway inhibitors

“…Although YAP inhibitors have been reported, 7 whether these agents are potent and selective enough to suppress the pathway with acceptable toxicity in patients is unclear. Therefore, the design and development of novel, more specific drugs that inhibit YAP may be warranted.…”