Structural insights into the dual-targeting mechanism of Nutlin-3

Multi-targeting therapy is an emerging strategy of drug discovery to improve therapeutic efficacy, safety and resistance profiles. In this study, we monitored the binding of a potent MDM2 Inhibitor Nutlin-3 with anti-apoptotic Bcl-2 Family proteins using NMR spectroscopy. Our results showed the universal binding of Nutlin-3 with diverse anti-apoptotic Bcl-2 Family proteins. Taken together with the binding data for Nutlin-3 analogs, the structural model of the Bcl-X(L)/Nutlin-3 complex showed that the binding mode of Nutlin-3 resembles that of the Bcl-X(L)/Bcl-2 inhibitors, suggesting the molecular mechanism of transcription-independent mitochondrial Apoptosis by Nutlin-3. Finally, our structural comparison provides structural insights into the dual-targeting mechanism of how Nutlin-3 can bind to two different target proteins, MDM2 and anti-apoptotic Bcl-2 Family proteins in a similar manner.