In contrast, for the cyanoacrylamides RC-2 and RC-3, the addition of Ibrutinib led to To assess their proteomic selectivity, we incubated the PROTACs at 50 nM or 100 nM for 24 hours with Ramos cells, and followed the change in protein abundance via quantitative label-free proteomics (Fig. , Supp. Fig. ). In agreement with the western blot analysis, BTK was efficiently degraded by all the PROTACs we tested. NC-1, IR-1, IR-2 and RC-2 also degraded the known Ibrutinib off-targets CSK, LYN and BLK , while several other offtargets, such as LCK and PLK1, were not significantly affected. NC-1 showed the highest degradation potency against BTK, in agreement with western blot analysis. On the other hand, the only significant off-target of RC-3 was BLK (a covalent off-target of Ibrutinib) with no activity against the non-covalent off-targets CSK and LYN, representing enhanced selectivity, and in agreement with the reduced non-covalent affinity of RC-3 to BTK. No other significant off-targets were detected consistently (Supp. Dataset 1).