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

Authors: 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

Published In Cell Chem Biol, (2021 04 15)

Abstract: 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.

PubMed ID: 33513350

MeSH Terms: Biological Products/chemistry; Biological Products/metabolism*; Humans; Molecular Structure; Proteomics*; Ubiquitin-Protein Ligases/metabolism*; Ubiquitination