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.