Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function

The translation of functionally active natural products into fully synthetic small-molecule mimetics has remained an important process in medicinal chemistry. We recently discovered that the terpene natural product nimbolide can be utilized as a covalent recruiter of the E3 ubiquitin ligase RNF114 for use in targeted protein degradation—a powerful therapeutic modality within modern-day drug discovery. Using activity-based protein profiling-enabled covalent ligand-screening approaches, here we report the discovery of fully synthetic RNF114-based recruiter molecules that can also be exploited for PROTAC applications, and demonstrate their utility in degrading therapeutically relevant targets, such as BRD4 and BCR-ABL, in cells. The identification of simple and easily manipulated drug-like scaffolds that can mimic the function of a complex natural product is beneficial in further expanding the toolbox of E3 ligase recruiters, an area of great importance in drug discovery and chemical biology. [Display omitted] •We have identified a fully synthetic covalent ligand EN219 that targets RNF114•We show that EN219 mimics the mode of action exploited by natural product nimbolide•We show that EN219 can be used as an RNF114 recruiter in degrader applications Using activity-based protein profiling-enabled covalent ligand-screening approaches, Luo et al. have discovered a fully synthetic RNF114 E3 ligase recruiter that can be used in targeted protein degradation applications.