To assess the PROTACs efficiency in a clinically relevant model we tested their ability to induce BTK degradation in primary cells from chronic lymphocytic leukemia (CLL) patients. The PROTACs displayed potent degradation with DC50's < 100 nM, with NC-1 and IR-2 reaching higher degradation levels than RC-2 and RC-3 (Fig. ). While we observed potent degradation by covalent PROTACs, it was still not clear if and how the covalent bond contributes to the degradation process. Due to the high non-covalent binding affinity of Ibrutinib to BTK, it is possible that the degradation is induced primarily by reversible binding that occurs prior to covalent bond formation. A second related question was what is the dissociation rate of the covalent complexes formed by the cyanoacrylamides, and whether this rate can support catalytic degradation to the same degree as non-covalent binding.