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

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 sc

SUBMITTER: Luo M 

PROVIDER: S-EPMC8052289 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature