Construction of PROTAC molecules by the SuFEx reaction for inducing p300/CBP protein degradation

While there have been advancements in the development of innovative PROTACs with sophisticated linkers designed to meet specific requirements, studies on the structure-activity relationships (SAR) of linker length remain a fundamental priority. Although several reliable chemistries for connecting the two ligands-one targeting the protein and the other for E3 ubiquitin ligase-have been established, the potential for utilizing various other methods still needs exploration. In this work, we introduced a concept that employs the SuFEx reaction, a novel family of click chemistry, to quickly construct a small PROTAC library for protein degradation. This was achieved by amidating a sulfonyl fluoride or fluorosulfate precursor (modified with the p300/CBP ligand CPI644) with CRBN ligands that possess amino-carbon chains of varying lengths. The protein degradation effects of the PROTACs created through this strategy were further validated using the p300/CBP overexpressed MDA-MB-468 cell line.