Screening of peptide inhibitors targeting YAP-TEAD4 interaction: affinity evaluation and anti-AML cell activity

Aberrant activation of YAP-TEAD4 drives tumorigenesis, progression, and chemoresistance. Disrupting their interaction serves as an alternative anticancer strategy, with peptides better adapting to the large, flat interaction interface. In this study, the peptides 1-4 were screened from the peptide database via pharmacophore modelling, molecular docking, and interaction analysis. Subsequently, affinity experiments showed that among the peptides 1-4, peptide-4 possessed the lowest <i>K</i>_d values (<i>K</i>_d = 5.08 ± 0.42 nM) measured by MST and exhibited the binding affinity for TEAD4. MD simulations further demonstrated that peptide-4 stably bound to the TEAD4. MTT assays showed that peptide-4 suppressed AML-193 cell viability with an IC₅₀ of 0.65 ± 0.04 μM. RT-qPCR assays demonstrated that Peptide-4 significantly downregulated the mRNA expression levels of <i>CTGF</i> and <i>CYR61</i>. In conclusion, the data demonstrated that the peptide-4 may serve as a promising candidate to disrupt the YAP-TEAD4 interaction and enhance biological activity in AML-related cellular models.