A multicomponent reaction-based peptide stapling approach generated stapled peptides with potent dual inhibition of MDM2 and MDMX — two key proteins that disable the p53 tumor suppressor.
Dual MDM2/MDMX inhibitionMCR-stapled peptides simultaneously block both cancer-promoting proteins from disabling p53
What the researchers found
MCR-based stapled peptides achieved potent dual antagonism of MDM2 and MDMX binding to p53, with crystal structures demonstrating direct staple-protein interactions that contribute to binding affinity.
Why it matters
MDM2 and MDMX both suppress p53, and dual inhibition is needed to fully reactivate this tumor suppressor. This versatile stapling method enables rapid generation of diverse, potent dual inhibitors.
The numbers in context
Dual MDM2/MDMX antagonists; multiple cocrystal structures; Ugi multicomponent reaction stapling
How the study worked
Multicomponent reaction (Ugi) peptide stapling with diversity generation at the cross-linker. Activity assessed by fluorescence polarization, microscale thermophoresis, and 2D NMR. Multiple co-crystal structures solved with MDM2.
Who was studied
Not applicable (chemistry and structural biology study)
What this study cannot tell us
In vitro biochemical and structural studies only. No cell-based or animal data on anti-cancer activity. Pharmacokinetics, cell penetration, and in vivo stability not assessed.
How to read the evidence
Preliminary — strong biochemical and structural data but no cellular or in vivo anti-cancer evidence.
When this study was published
Published in 2020; stapled peptide drug development continues with several candidates in clinical trials for various targets.
The bigger picture
Reactivating p53 is one of the most pursued strategies in cancer drug development. Stapled peptides offer advantages over small molecules for targeting the large, flat protein-protein interaction surfaces involved.
Questions still open
- Do these MCR-stapled peptides penetrate cancer cell membranes and reactivate p53 in cellular assays?
- How do the pharmacokinetic properties compare to existing stapled peptide drugs?
- Can this MCR stapling approach be applied to other protein-protein interaction targets?
Common questions
What are stapled peptides?
Why target both MDM2 and MDMX?
Read the original research
Multicomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein-Protein Interactions.
Angewandte Chemie (International ed. in English), 59(13), 5235-5241
Citation
Ricardo, Manuel G; Ali, Ameena M; Plewka, Jacek; Surmiak, Ewa; Labuzek, Beata; Neochoritis, Constantinos G; Atmaj, Jack; Skalniak, Lukasz; Zhang, Ran; Holak, Tad A; Groves, Matthew; Rivera, Daniel G; Dömling, Alexander. (2020). Multicomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein-Protein Interactions.. Angewandte Chemie (International ed. in English), 59(13), 5235-5241. https://doi.org/10.1002/anie.201916257