Advances in reversible covalent kinase inhibitors

Reversible covalent kinase inhibitors (RCKIs) are a class of novel kinase inhibitors attracting increasing attention because they simultaneously show the selectivity of covalent kinase inhibitors yet avoid permanent protein-modification-induced adverse effects. Over the last decade, RCKIs have been reported to target different kinases, including Atypical group of kinases. Currently, three RCKIs are undergoing clinical trials. Here, advances in RCKIs are reviewed to systematically summarize the characteristics of electrophilic groups, chemical scaffolds, nucleophilic residues, and binding modes. In so doing, we integrate key insights into privileged electrophiles, the distribution of nucleophiles, and hence effective design strategies for the development of RCKIs. Finally, we provide a further perspective on future design strategies for RCKIs, including those that target proteins other than kinases.