Development of Second-Generation Acyl Silane Photoaffinity Probes for Cellular Chemoproteomic Profiling

Le résumé fourni par la source

Deconvolution of the protein targets of hit compounds from phenotypic screens, often conducted in live cells, is critical for understanding mechanism of action and identifying potentially hazardous off-target interactions. While photoaffinity labeling and chemoproteomics are long-established approaches for discovering small-molecule-protein interactions in live cells, there are a relatively small number of photoaffinity labeling strategies that can be applied for chemoproteomic target identification studies. Recently, we reported a novel chemical framework for photoaffinity labeling based on the photo-Brook rearrangement of acyl silanes and demonstrated its ability, when appended to protein-targeting ligands, to label recombinant proteins. Here, we report the application of these probes to live cell photoaffinity workflows, demonstrate their complementarity to current state-of-the-art minimalist diazirine-based photoaffinity probes, and introduce a modular synthetic route to access acyl silane scaffolds with improved labeling properties.

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