The motivation for developing reversible covalent PROTACs lies in the combination of the advantages encompassed by covalent binding, such as increased potency and selectivity, while maintaining the reversibility that is considered important for the catalytic nature of PROTAC efficacy. Several previous studies reported non-covalent PROTACs against BTK and some indicated that irreversible binding might be detrimental to the activity of covalent PROTACs . In this work we tested whether cyanoacrylamide reversible covalent binders could serve as potent PROTACs. Our results show that both acrylamides and cyanoacrylamides can function as potent and selective PROTACs, including in patient-derived cell lines (Fig. ), with the irreversible IR-2 being amongst the most potent BTK PROTACs reported to date. Still, the non-covalent PROTAC NC-1 outperformed IR-2.