Downsizing Electrophilic MAX-Derived Helical Zipper Peptides to Covalently Bind and Degrade Oncogenic MYC

Abstract

Oncogenic MYC is a transcription factor that is difficult to inhibit. However, precise positioning of an acrylamide electrophile in MAX to covalently bond to the unique Cys438 in MYC, enabled shortening and optimizing of MAX-derived, helix-constrained peptides with high-affinity and selectivity. These covalent inhibitors block MAX-MYC interaction, while ester prodrugs trigger MYC degradation, suppressing cancer cell migration and proliferation.