biostudies-literatureLuo MNIEHS NIH HHSMark Foundation For Cancer ResearchNational Cancer InstituteNCI NIH HHSNovartis Institutes for BioMedical ResearchNIGMS NIH HHS559-566.e15https://www.ebi.ac.uk/biostudies/studies/S-EPMC8052289biostudies-literatureUnknown28(4)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 scCell chemical biologyChemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function.PMC8052289R01 CA240981F31 CA239327R01 GM136945F99 CA253717R01 ES028096Tong BNomura DKSchirle MLuo MMaimone TJTallarico JAMcKenna JMBrittain SMSpradlin JNBoike LfalseChemoproteomics-enabled discovery of covalent RNF114-based degraders that mimic natural product function.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 sc2021-01-01T00:00:00Z2021 Apr2026-05-02T22:40:44.806Z2025-04-04T13:30:32.661ZS-EPMC80522893351335010.1016/j.chembiol.2021.01.005