A YAP-derived peptide blocks YAP-TEAD signaling and suppresses cell proliferation

Yes-associated protein (YAP), a pivotal transcriptional co-activator in cell growth regulation, exerts its function through interactions with transcriptional factors like TEAD. Ectopic activation of YAP causes excessive cell proliferation, leading to multiple human diseases, including cancers. However, current pharmacological YAP inhibition lacks specificity and may have unintended effects, necessitating the development of direct YAP-derived inhibitors. In this study, we designed a novel YAP-derived peptide, TBDi, that specifically disrupted YAP-TEAD interaction and exhibited robust inhibition of TEAD activity. Mechanistically, TBDi directly binds to TEAD, blocking the physical interaction between YAP and TEAD. Transcriptomic analysis revealed that TBDi significantly altered gene expression profiles associated with TEAD activity, including downregulation of signature genes like CYR61 and CTGF. Functionally, TBDi emerged as a potent suppressor of cell proliferation, inhibiting cell proliferation to a degree comparable to YAP/TAZ knockdown. Altogether, our study not only identifies TBDi as a promising tool to block YAP-TEAD axis, but also offers insights for potential therapeutic interventions in diseases.