Degradation of Rat Sarcoma Proteins Targeting the Post-Translational Prenyl Modifications via Cascade Azidation/Fluorination and Click Reaction

摘要

Protein degradation is emerging as a powerful strategyto modulateprotein functions and alter cellular signaling pathways. Proteolysis-targetingchimeras (PROTACs) have been used to degrade a range of "undruggable"proteins in cells. Here, we present a type of chemically catalyzedPROTAC to induce rat sarcoma (RAS) degradation based on the chemistryof post-translational prenyl modification. Trimethylsilyl azide andSelectfluor were used to chemically tag the prenyl modification onCaax motif of RAS protein, and a sequential click reaction was appliedusing the propargyl pomalidomide probe to degrade the prenylated RASin several cells. Thus, this approach was successfully applied todegrade RAS in multiple cancer cell lines including HeLa, HEK 293T,A549, MCF-7, and HT-29. This novel approach targeting RAS'spost-translational prenyl modification to induce RAS degradation byemploying the sequential azidation/fluorination and click reactionhas been demonstrated efficiently and highly selectively, expandingPROTAC toolsets in the study of disease-relevant protein targets.