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 activitybased 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.Y

Automated summary

This study found that the natural product nimbolide can be used as a recruiter of the E3 ubiquitin ligase RNF114 for targeted protein degradation, which is important in modern drug discovery. Through activity-based protein profiling-enabled ligand screening, fully synthetic molecules mimicking nimbolide were discovered, showing potential for degrading therapeutic targets.