Molecular design of Stat3‐derived peptide selectivity between BET proteins Brd2 and Brd4 in ovarian cancer

Stat3 signaling has been recognized as a potential therapeutic target of human ovarian cancer. The signaling is transducted through the peptide‐medicated interaction of Stat3 with BET family members Brd2 and Brd4 –– 2 highly homologous proteins involved in differential downstream pathways. Here, we reported a successful design of peptide selectivity between the Brd2 and Brd4. The design resulted in 3 linear peptides SMSLQCX YLGVA, QSKVLTX SYWGA, and RQCNLGX LYMNY with high or moderate selectivity for Brd2 over Brd4 (S = 3.3‐fold, 6.8‐fold, and 4.2‐fold, respectively) as compared with the native Stat3 peptide ²⁸¹HNLLRIX QFLQS²⁹² (S = 2.5‐fold). Structural analysis revealed that peptide N‐terminus and hydrogen bonds play important roles in the peptide interaction stability and specificity with Brd2 and Brd4. This study would help to establish an integrated in silico‐in vitro method for rational molecular design of peptide ligand selectivity between homologous protein receptors.