In parallel to this publication, Guo et al. have also reported cyanoacrylamide-based BTK degraders, using a different linker design. For that series of PROTACs the cyanoacrylamides were much more potent than the equivalent noncovalent and acrylamide PROTACs, which they attribute to significantly higher cell penetration of the cyanoacrylamides. Their study thus support the use of reversible covalent PROTACs but makes it difficult to draw conclusions regarding the role of the covalent bond in the degradation. Here, RC-3 and NC-1 penetrated the cells to a similar degree, and both bind BTK reversibly, with RC-3 showing much better IC50 (Fig. ). However, NC-1 is still a more efficient BTK degrader. We suggest two hypotheses for this discrepancy: First, the noncovalent NC-1 has a much less rigid linker than IR-2 and RC-3, with free rotation around the bond proximal to the amide linkage. This flexibility may aid the PROTAC in adopting the optimal configuration for the ternary complex formation and for ubiquitination, or increase the stability of the interaction of the BTK-PROTAC complex with the E3 ligase , which is likely more relevant to degradation efficiency, and may also explain the ability of NC-1 to compete with thalidomide (Fig. ) compared to the other PROTACs. Second, the non-covalent NC-1 has a rapid binding and dissociation equilibrium -in the presence of preincubated NC-1, Ibrutinib labels BTK fully within 1 hour (Supp. Fig. ). Therefore, NC-1 can bind BTK in the cell, promote the formation of the ternary complex to induce ubiquitination, and quickly dissociate to bind more BTK molecules, even before the ubiquitinated BTK undergoes proteasomal degradation. The cyanoacrylamides tested here dissociate in timescales of 10-20 hours, similar to the residence times observed for other cyanoacrylamide inhibitors . Therefore, they can only be recycled after the bound BTK molecule has been degraded, resulting in less efficient catalysis.