Abstract Proteolysis-targeting chimeras (PROTACs) represent a transformative therapeutic modality, yet the viability of covalent PROTACs remains debated, as irreversible binding seemingly contradicts the catalytic mechanism of action. Here, we develop and characterize PSIRC3, a potent covalent PROTAC for Bruton’s tyrosine kinase (BTK). PSIRC3 induces selective BTK degradation with a sub-nanomolar DC50 of 0.75 nM and a Dmax of 85%, while its non-covalent counterpart is inactive.
