Triadic Electrophilic Centers Specifically Bind to SMO Transmembrane Domain to Inhibit the Hedgehog Pathway

Abstract

Abstract Designing drugs to target overexpressed membrane protein smoothened (SMO) to selectively inhibit the Hedgehog signaling pathway represents a promising approach to achieving effective chemotherapy. Currently, only three organic small molecular inhibitors of SMO have been approved for clinically targeted therapy. Herein, we demonstrate a novel strategy to anchor SMO by designing metallodrugs ( RuSe , OsSe , RuIP , OsIP ) containing triadic electrophilic centers (─N(δ − )─X(δ + )─N(δ − )─). In vitro and in vivo experiments validated that the designed triadic electrophilic center drugs could selectively inhibit the activity of SMO, blocking the Hedgehog signaling pathway and effectively killing tumors. Through theoretical calculations combined with experimental data, we verified that the interaction between the protein and drugs increases the polarization of the triadic electrophilic centers. The drugs utilize dual electrophilic centers to fix the binding and use the third electrophilic center insert to the swinging hinge region between TM5 and TM6 of the 7‐transmembrane domain of SMO. This strengthens the π‐cation lock binding between the transmembrane peptide chains, ultimately inhibiting the mobility of the transmembrane peptide chains and thereby inhibiting SMO activity. This work provides a new strategy for designing SMO specific targeted drugs, offering new hope for clinically targeted therapies.