Yu Kawamata†1, Keun Ah Ryu†2, Gary N. Hermann†1, Alexander Sandahl1, Julien C. Vantourout1, Aleksandra K. Olow3, La-Tonya A. Adams4, Eva Rivera-Chao1, Lee R. Roberts2, Rob C. Oslund*2, Olugbeminiyi O. Fadeyi*2, Phil S. Baran
Target identification is a critical pillar within the drug discovery process that involves deconvoluting the protein target of a pharmacologically active small molecule ligand. While photoaffinity labeling strategies have become the benchmark for target deconvolution of small molecules owing to their reliance on external activation to induce covalent protein capture, the process of target identification remains one of the most technically challenging aspects of early drug discovery. Thus, there is a strong demand for new technologies that allow for controlled activation of chemical probes to covalently label their protein target. Here, we introduce an electroaffinity labeling (ECAL) platform which leverages the use of a small, redox-active diazetidinone (DZE) functional group to enable chemoproteomic-based target identification of pharmacophores within live cell environments.