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

Abstract

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.