PROTACs based on CRBN and IAP binders, which were inactive and were also substituted acrylamides. These PROTACs harbored a piperazine moiety in the linker, attached one carbon away from the acrylamide group, which may affect reactivity and PROTAC binding. However, in vitro kinase assays using wild type and mutant BTK had similar results to those reported here, with their acrylamide PROTAC exhibiting essentially the same IC50 towards BTK as the non-covalent counterpart. Therefore, the covalent PROTACs tested by Tinworth et al. most likely also have formed covalent bonds inefficiently, and their inactivity may have resulted from issues such as permeability, stability or an unfavorable geometry. Conversely, Xue et al. recently developed unsubstituted acrylamide BTK PROTACs that covalently engaged BTK and degraded it the cell, albeit not to 100%. Along with our study this indicates that measurement of the relative rates of covalent bond formation and degradation is needed to estimate how covalent binding affects PROTAC activity.