Avoiding drug resistance through extended drug target interfaces: a case for stapled peptides

Area of Science:

• Oncology
• Drug Discovery
• Molecular Biology

Background:

• Cancer drug resistance, often due to target protein mutations, limits therapeutic efficacy.
• Stapled peptides are emerging as potent inhibitors of protein-protein interactions, offering a novel therapeutic strategy.
• The HDM2-p53 interaction is a key target in cancers with wild-type p53.

Purpose of the Study:

• To investigate the potential for clinical resistance to stapled peptide inhibitors targeting HDM2.
• To compare the resistance profiles of stapled peptides with small molecule inhibitors against HDM2.

Main Methods:

• Generated and screened a library of randomly mutated HDM2 proteins.
• Assessed the binding of a stapled peptide inhibitor (PM2) and a small molecule inhibitor (Nutlin) to mutated HDM2 variants.

Main Results:

• No point mutations were found that selectively abrogated binding of the stapled peptide PM2 to HDM2.
• Previously identified mutations that confer resistance to the small molecule Nutlin did not affect PM2 binding.
• PM2 demonstrates high structural mimicry of p53, contributing to its resilience.

Conclusions:

• Stapled peptide inhibitors exhibit potential resilience to target mutations, suggesting a reduced risk of clinical resistance.
• This inherent resistance profile could be advantageous for the clinical application of stapled peptide therapeutics.
• The findings highlight the distinct resistance mechanisms associated with different drug modalities targeting the same protein-protein interaction.