Abstract
The translation of natural product function to fully synthetic small molecules has remained an important process in medicinal chemistry for decades resulting in numerous FDA-approved medicines. 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 (TPD) – a powerful therapeutic modality within modern day drug discovery. Using activity-based protein profiling-enabled covalent ligand screening approaches, we herein 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.
Competing Interest Statement
JAT, JMK, MS, SMB are employees of Novartis Institutes for BioMedical Research. This study was funded by the Novartis Institutes for BioMedical Research and the Novartis-Berkeley Center for Proteomics and Chemistry Technologies. DKN is a co-founder, shareholder, and adviser for Frontier Medicines.