Abstract LB-056: A novel cyclic peptide inhibitor targeting the YAP-TEAD protein-protein interaction shows potent anti-tumor effect in a variety of human malignancies including mesothelioma

Abstract

Abstract The Hippo signaling pathway plays an important role in organ size control. Dysregulations of this pathway have been implicated in human cancer. Oncoprotein YAP is a major downstream effector molecule for Hippo pathway and has no intrinsic DNA binding domain. The functionality of YAP depends on the interaction of YAP with transcription factor TEAD in cell nucleus. Inhibitors targeting YAP-TEAD PPI could rectify abnormal Hippo pathway, leading to tumor remission. Screening through a carefully designed peptide library derived from the YAP protein, we have successfully identified potent YAP inhibiting peptides (YIP). Surface plasmon resonance (SPR) showed that the YIP bind to TEAD with high affinity in the nM-pM (KD) range. Subsequently, the binding interaction was confirmed by Pull-down experiments. In cell-based assays, YIP inhibited cell proliferation in various cancer cell lines at low µM (IC50) range. Furthermore, cellular nuclear tests indicated that YIP could penetrate into the nucleus and inhibited YAP-TEAD interaction by TEAD-luciferase assay in a dose dependent manner. In several s.c. xenograft animal models, a lead YIP strongly suppressed the tumour growth including NF-2 mutant mesothelioma cells. The lead YIP has good drug-like pharmacological properties and represents a promising candidate targeting the Hippo pathway as an effective treatment for cancers. Citation Format: YI P. HU, Yinghua M. Wang, Daniel Lee, Yi Ren. A novel cyclic peptide inhibitor targeting the YAP-TEAD protein-protein interaction shows potent anti-tumor effect in a variety of human malignancies including mesothelioma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-056.