Appendage- and Scaffold-Diverse Electrophilic and Photoreactive Probes for Integrated Phenotypic Screening-Target Identification Campaigns via a Minimalist Bifunctional Isocyanide.

One of the grand challenges in chemical biology is identifying a small-molecule modulator for all proteins within a proteome. To expand the variety and number of ligandable proteins for drug discovery, the objective of this study was to synthesize and evaluate the protein target profiles of electrophilic and photoreactive fully functionalized small-molecule probes (FFSMPs) featuring increased scaffold-, appendage-, and protein-reactive functional group (PRFG) diversity. FFSMPs contain: (1) a protein-binding motif, (2) an electrophilic or photoreactive PRFG for target protein capture, and (3) a terminal alkyne for click chemistry-based proteomic applications.