“…Over the past decade, chemical proteomics has emerged as a powerful technology for target discovery, and many new targets have been identified by means of this technology and have been used in drug development. − However, a large fraction of the proteome is still inaccessible with current chemical probes, and these proteomic entities remain defined as undruggable targets. − Covalent inhibitors have received considerable attention due to their remarkable pharmaceutical properties, but the reactive warhead of covalent drugs are limited to α,β-unsaturated amides. , Consequently, it is highly desirable to develop novel chemical probes, especially novel electrophilic warheads that can be exploited in proteome profiling experiments . Recently, several novel reactive groups such as heteroaromatic sulfones, sulfonium ions, 2-sulfonylpyridine, sulfur triazole, 2-methylthio pyridiniumoxazoline ion, and bicyclobutane carboxylic amide, which target nucleophilic residues in proteins, such as cysteine, lysine, and tyrosine have been developed, and many of them have been used in the development of new types of covalent inhibitors and in target discovery . We recently developed a 2H-3-phenyl-azirine, terminal ynamide, and a diaryltetrazole for chemoselective modification of carboxylic acid residues in live cells. − To further expand the toolbox of reactive warheads, we developed here a suite of novel electrophiles for proteome profiling and the potential of developing new types of covalent inhibitors.…”