A Proximity-Triggered Strategy toward Transferable Proteolysis Targeting Chimeras

Over the past 20 years, great efforts have been invested in developing site-specific approaches to protein modification to dissect protein functions directly and accurately. Here, we report a proximity-triggered group transfer strategy from a sulfonium warhead to a Cysteine (Cys) residue of the target protein. With a guiding ligand, cargoes could be transferred selectively from a sulfonium center onto the Cys residue in the vicinity of their binding interface. The successful thalidomide transfer of sulfonium 1-X could be applied intracellularly for epidermal growth factor receptor degradation, highlighting the potential of group transfer strategy as a suite of chemical biology studies, including cell imaging, protein profiling, and protein degradation by simply employing different transferrable groups. [GRAPHICS] .

Automated summary

This article introduces a proximity-triggered group transfer strategy, which enables the transfer of groups from a sulfonium warhead to a Cysteine residue near the binding interface. Successful intracellular transfer of sulfonium 1-X was achieved, leading to the degradation of epidermal growth factor receptors and highlighting the potential of this strategy in chemical biology studies.