Target engagement and HDAC degradation selectivity profile of 2 and 1j. For further investigations, we selected the two most effective HDAC1 degraders from this set (2 and 1j), as they also demonstrated the highest antiproliferative activity. As target engagement is crucial for targeted protein degradation, we next investigated the HDAC inhibition efficiency of the PROTAC hits. To distinguish between their effects on the various isoforms, we evaluated the inhibitory activity on representative isoforms from different HDAC classes, namely HDAC1, 2, 4 and 6 (Table ). Compound 2 demonstrated comparable inhibition results as A6. However, 1j, the most potent degrader, exhibited comparatively weaker inhibition of all tested isoforms. The half-maximal inhibitory concentration (IC50) is consistently ~4-8 times higher than that of 2.