In 2013, Serafimova assessed a series of electrophilic molecules that engaged non-catalytic cysteines in a covalent manner, but with variable target residence times, driven by the various stabilizing interactions of the molecule in the protein binding site. These reversible covalent inhibitors were shown to rapidly dissociate from common thiols while maintaining sustained inhibition of a target protein even after washout. This technology, therefore, has the potential to allow medicinal chemists to fashion inhibitors with the potential for selectivity gained by inhibiting only targets with a conserved cysteine, and minimal exposure requirements inherent with covalent inhibition. The reversible covalent approach furthermore mitigates risk of irreversible binding to non-target cysteines or endogenous thiols, but also allows the potential to improve selectivity among targets sharing a common cysteine. This technology has been used to identify selective inhibitors of kinases such as BTK and FGFR as well as LMP7 subunit of the immunoproteasome. Based on our interest in BTK inhibition for the treatment of immune mediated disorders, we embarked on a drug development effort to identify reversible covalent inhibitors culminating in the identification of PRN473 for topical administration and PRN1008 (rilzabrutinib) as an oral BTK inhibitor currently in multiple phase 3 studies.