Stapled Peptide PROTACs Simultaneously Degrade Two Cancer-Promoting Proteins and Suppress Tumors in Mice | Research

The takeaway

A stapled peptide fused with a protein degradation tag (PROTAC) simultaneously destroyed both MDM2 and MDMX cancer proteins, reactivating the p53 tumor suppressor and shrinking colorectal tumors in mice.

Dual MDM2/MDMX degradation achieved
First stapled peptide-PROTAC to simultaneously destroy both p53-suppressing proteins, enabling durable tumor suppressor reactivation in colorectal cancer models

What the researchers found

The optimized stapled peptide-PROTAC hybrid SPMI-HIF2-1 showed similar binding affinity for both MDM2 and MDMX compared to its linear counterpart, but with higher helical content, improved proteolytic stability, better cellular permeability, and improved pharmacokinetics. In subcutaneous and orthotopic colorectal cancer xenograft models, SPMI-HIF2-1 effectively killed cancer cells and inhibited tumor progression through simultaneous atypical degradation of both MDM2 and MDMX, leading to durable p53 activation. Structural analysis confirmed the molecule simultaneously bound the target protein and E3 ligase in a ternary complex.

Why it matters

p53 is mutated or inactivated in more than half of all human cancers, and reactivating it is one of the most pursued goals in oncology. Previous approaches using peptide inhibitors of MDM2/MDMX were limited by poor stability and the rapid rebound of target proteins. SP-PROTACs solve both problems — they're stable enough to reach cancer cells and they permanently destroy (rather than just inhibit) the cancer proteins. This 'degrade rather than inhibit' paradigm could produce longer-lasting anticancer effects.

How the study worked

Researchers designed a series of stapled peptide-based PROTACs (SP-PROTACs) based on the PMI peptide, which has dual specificity for MDM2 and MDMX. They characterized binding affinity (fluorescence polarization assays), structural properties (helical content), proteolytic stability, cellular permeability, and pharmacokinetics. Anticancer efficacy was tested in both subcutaneous and orthotopic colorectal cancer xenograft mouse models. Structural modeling analyzed the ternary complex formation.

What this study cannot tell us

All efficacy testing was in mouse xenograft models using human colorectal cancer cells, which may not fully predict human responses. The pharmacokinetic improvements over linear peptides, while significant, still may not be sufficient for clinical use without further optimization. The atypical degradation mechanism needs further characterization. No toxicity or safety data were reported beyond tumor models. Clinical translation of stapled peptide-PROTACs faces manufacturing and formulation challenges.

How to read the evidence

This is a preclinical drug development study with in vitro characterization and in vivo efficacy in both subcutaneous and orthotopic mouse cancer models. The dual-model approach and mechanistic characterization are rigorous for preclinical work, but no human data exist.

When this study was published

Published in 2022 in Theranostics, this study is at the forefront of the rapidly evolving PROTAC and stapled peptide fields, with ongoing efforts to translate similar approaches to clinical trials.

The bigger picture

PROTACs (proteolysis-targeting chimeras) are one of the hottest areas in drug development, but most are small molecules with limited ability to target protein-protein interactions. Stapled peptides excel at disrupting protein-protein interactions but can't destroy their targets. This study bridges the two fields, creating a hybrid approach that could expand PROTAC technology to the vast number of cancer targets that are accessible to peptides but not small molecules. MDM2/MDMX dual degradation with p53 reactivation is a compelling proof-of-concept for this new drug class.

Questions still open

Could stapled peptide-PROTACs targeting MDM2/MDMX be combined with checkpoint immunotherapy for enhanced anticancer effects?
Can this SP-PROTAC platform be generalized to other protein-protein interaction targets beyond the p53 pathway?
What is the safety profile of simultaneous MDM2/MDMX degradation — could excessive p53 activation harm normal tissues?

Common questions

What is a PROTAC and how is it different from a regular drug?

Most drugs work by blocking a disease-causing protein — like putting a cork in a bottle. PROTACs (proteolysis-targeting chimeras) take a completely different approach: they tag the disease protein for destruction by the cell's own recycling machinery. The protein is permanently eliminated rather than temporarily blocked. This can produce longer-lasting effects and overcome resistance that develops when proteins simply get blocked.

Why combine stapled peptides with PROTACs?

Stapled peptides are chemically reinforced versions of natural peptides that are better at entering cells and resisting breakdown. PROTACs are molecular tags that mark proteins for destruction. Alone, each technology has limitations — peptides can't destroy targets, and most PROTACs can't disrupt protein-protein interactions. By fusing the two, researchers created a molecule that enters cancer cells, binds tightly to cancer-promoting proteins (MDM2 and MDMX), and tags them both for permanent destruction.

Read the original research

Design of stapled peptide-based PROTACs for MDM2/MDMX atypical degradation and tumor suppression.

Theranostics, 12(15), 6665-6681

View on PubMed ↗Publisher’s paper ↗

Citation

Chen, Si; Li, Xiang; Li, Yinghua; Yuan, Xing; Geng, Chenchen; Gao, Songyan; Li, Jinyang; Ma, Bohan; Wang, Zhe; Lu, Wuyuan; Hu, Hong-Gang. (2022). Design of stapled peptide-based PROTACs for MDM2/MDMX atypical degradation and tumor suppression.. Theranostics, 12(15), 6665-6681. https://doi.org/10.7150/thno.75444