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Multi-targeting therapy is a new approach in drug discovery aimed at enhancing effectiveness, safety, and resistance against treatments.
The study utilized NMR spectroscopy to observe how the MDM2 inhibitor Nutlin-3 binds to anti-apoptotic Bcl-2 proteins, revealing a common binding interaction.
The findings suggest that Nutlin-3 can induce mitochondrial apoptosis via a dual-targeting mechanism, binding both to MDM2 and Bcl-2 proteins in a similar way.
Article Abstract
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.
