Theoretically, reversible covalent PROTACs can benefit from both the enhanced potency, selectivity, and long duration of action that accompany covalent bond formation , without compromising the sub-stoichiometric activity of PROTACs. In this work we set out to test this hypothesis by the design of cyanoacrylamide-based reversible covalent PROTACs. To this end, we selected Bruton's tyrosine kinase (BTK), which is an established target for non-covalent PROTACs , and systematically tested a series of reversible covalent PROTACs along with their irreversible covalent and non-covalent PROTAC analogs.