Luo, Mai, Spradlin, Jessica, Boike, Lydia, Tong, Bingqi, Brittain, Scott, McKenna, Jeffrey, Tallarico, John, Schirle, Markus, Maimone, Thomas and Nomura, Dan (2021) Chemoproteomics-Enabled Ligand Screening Yields Covalent RNF114-Based Degraders that Mimics Natural Product Function. Cell chemical biology. ISSN 24519456

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 realize the discovery of fully synthetic RNF114-based recruiter molecules that can also be exploited for PROTAC applications, and demonstrate their utility in degrading oncology 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.

Item Type:	Article
Date Deposited:	23 Feb 2021 00:45
Last Modified:	23 Feb 2021 00:45
URI:	https://oak.novartis.com/id/eprint/43026