In vivo target identification of benzoisothiazol-3(2H)-one and isothiazolo[5,4-b]pyridine3(2H)-one by click chemistry

Isothiazole compounds have been shown to target histone acetyl transferases in vitro and are promising anticancer drugs. In addition, these compounds have been known to exhibit antimicrobial activity, although the molecular targets remain unidentified. Here, we present a strategy for using alkyne-derivatised isothiazole compounds, which retain both their antimicrobial and inhibitory activity against histone acetyl transferases, as activity probes for identifying their target proteins in vivo using click chemistry followed by identification by mass-spectrometry. The aim of this interdisciplinary project within the COST network is mechanistic understanding of these isothiazole drugs as well as the proteomic identification of candidate drug targets for the development of improved antibiotic and anticancer compounds.