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

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.