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 Kd values (Kd = 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 CTGF and CYR61. 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.