Sequential Azidation/Azolation of Prenylated Derivatives and a Click Reaction Enable Selective Labeling and Degradation of RAS Protein.

We propose the introduction of the azido and azo-functionalities into prenylated derivatives under mild conditions in a selective and efficient way. Upon protocol establishment and substrate scope determination, we apply this method to prenylated protein (citronellol-BSA) labeling, chemical pulldown, and enrichment. Eventually, we achieve the degradation of RAS on MCF-7 and HeLa cell lines by employing the well-designed probe von Hippel-Lindau derivatives C4 through the sequential azidation/azolation and click-reaction (SACR) pathway targeting the prenyl functionality attached to the Caax motif of the tested RAS protein. This method displays great potential in regulation of prenylated molecules.