The clinical utility of targeting kinases with covalent drugs has been firmly established, as exemplied by the irreversible kinase inhibitors, afatinib, ibrutinib, and rociletinib. More broadly, targeting a noncatalytic cysteine with an electrophilic inhibitor often results in enhanced potency and selectivity. Motivated by a desire to explore the chemistry of thiol-reactive electrophiles under physiological conditions, we initiated a study of Michael acceptors bearing substituents with increasing electron withdrawing capacity. We found that 2-cyanoacrylamides react with simple thiols in a rapidly reversible manner, suggesting that the intrinsically labile nature of the cysteine/cyanoacrylamide bond could be exploited in the design of reversible covalent inhibitors. These concepts have led to the design of ultra-selective kinase inhibitors with slow dissociation kinetics.

From serendipity to clinical trials: Discovery of reversible covalent kinase inhibitors

253rd National Meeting (2017)

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