# Covalent Peptide‐Based N‐Myc/Aurora‐A Inhibitors Bearing Sulfonyl Fluoride Warheads

## TL;DR

Researchers developed a new type of drug that targets a specific protein interaction in neuroblastoma, a childhood cancer, using a covalent inhibitor that selectively binds to a key protein.

## Contribution

The study introduces a novel covalent inhibitor with a sulfonyl fluoride warhead that selectively targets the N-Myc/Aurora-A protein interaction.

## Key findings

- Peptidomimetics with sulfonyl fluoride warheads selectively label Aurora-A in a recognition-directed manner.
- The inhibitors effectively block the N-Myc/Aurora-A protein–protein interaction.
- This approach provides insights for developing drugs to treat neuroblastoma.

## Abstract

Orthosteric inhibition of the N‐Myc/Aurora‐A protein–protein interaction (PPI) represents a potential mechanism by which degradation of N‐Myc can be induced, given its interaction with Aurora‐A competes with the factors that tag it for proteasomal degradation. As such, this would constitute an approach for the development of drugs to treat neuroblastoma, a childhood cancer that depends upon N‐Myc. Reactive electrophiles have proven useful in the context of targeted covalent inhibitors, and in this work, we sought to improve the potency of a previously identified N‐Myc‐derived peptide by introducing a sulfonyl fluoride warhead. We successfully demonstrated selective labelling of Aurora‐A using the resultant peptidomimetics and established this labelling as recognition‐directed, providing valuable insight for further future development of N‐Myc peptidomimetics and further broadening the use of aryl sulfonyl fluoride warheads in the context of peptidomimetic PPI inhibitors.

N‐Myc‐derived peptidomimetics bearing aryl sulfonyl fluoride warheads were shown to act as effective N‐Myc/Aurora‐A PPI inhibitors, selectively labelling Aurora‐A in a recognition‐directed manner.