Nitriles: an attractive approach to the development of covalent inhibitors

Nitriles have broad applications in medicinal chemistry, with more than 60 small molecule drugs on the market containing the cyano functional group. In addition to the well-known noncovalent interactions that nitriles can perform with macromolecular targets, they are also known to improve drug candidates' pharmacokinetic profiles. Moreover, the cyano group can be used as an electrophilic warhead to covalently bind an inhibitor to a target of interest, forming a covalent adduct, a strategy that can present benefits over noncovalent inhibitors. This approach has gained much notoriety in recent years, mainly with diabetes and COVID-19-approved drugs. Nevertheless, the application of nitriles in covalent ligands is not restricted to it being the reactive center, as it can also be employed to convert irreversible inhibitors into reversible ones, a promising strategy for kinase inhibition and protein degradation. In this review, we introduce and discuss the roles of the cyano group in covalent inhibitors, how to tune its reactivity and the possibility of achieving selectivity only by replacing the warhead. Finally, we provide an overview of nitrile-based covalent compounds in approved drugs and inhibitors recently described in the literature.