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

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.