PROTACs by linking a simplified HDAC ligand derived from A6, with changes in the linker and ZBG, to either 5-fluorothalidomide or VH032 via different linkers. Among these eight PROTACs, the CRBNengaging molecules 17a-d induced selective degradation of HDAC6, while other isoforms were not degraded. The VH032-based PROTACs did not induce degradation of any of the analyzed isoforms, although binding to HDAC1-3 and HDAC6 was confirmed through enzyme inhibition assays. The lack of degradation might be due to insufficient ternary complex formation which is crucial for the degradation of the POI. Compound 17c triggered strong HDAC6 degradation in MM.1S cells (91% at 0.5 µM), with a DC50 of 14 nM for HDAC6. Notably, 17c selectively degrades HDAC6 without affecting other HDAC isoforms, as confirmed by immunoblot analysis and quantitative proteomics. An N-methylated non-degrading negative control, NC-17c, was synthesized and tested head-to-head with 17c for HDAC1 and HDAC6 degradation and α-tubulin hyperacetylation. It could be shown that in contrast to 17c, NC-17c neither affected HDAC6 levels nor induced hyperacetylation of α-tubulin. To confirm that HDAC6 degradation is mediated by the ubiquitin-proteasome system (UPS) we tested 17c