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

Protein degradation is emerging as a powerful strategy to modulate protein functions and alter cellular signaling pathways. Proteolysis-targeting chimeras (PROTACs) have been used to degrade a range of "undruggable" proteins in cells. Here, we present a type of chemically catalyzed PROTAC to induce rat sarcoma (RAS) degradation based on the chemistry of post-translational prenyl modification. Trimethylsilyl azide and Selectfluor were used to chemically tag the prenyl modification on Caax motif of RAS protein, and a sequential click reaction was applied using the propargyl pomalidomide probe to degrade the prenylated RAS in several cells. Thus, this approach was successfully applied to degrade RAS in multiple cancer cell lines including HeLa, HEK 293T, A549, MCF-7, and HT-29. This novel approach targeting RAS's post-translational prenyl modification to induce RAS degradation by employing the sequential azidation/fluorination and click reaction has been demonstrated efficiently and highly selectively, expanding PROTAC toolsets in the study of disease-relevant protein targets.