494764-44-2Relevant articles and documents
Chemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function
Luo, Mai,Spradlin, Jessica N.,Boike, Lydia,Tong, Bingqi,Brittain, Scott M.,McKenna, Jeffrey M.,Tallarico, John A.,Schirle, Markus,Maimone, Thomas J.,Nomura, Daniel K.
, p. 559 - 15,566 (2021)
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.
