The subsequent hydrazine monohydrate-mediated deprotection released the resin-bound hydroxylamine, enabling its coupling with Fmoc-7-aminoheptanoic acid which was facilitated by HATU and HOBt. This step formed the zinc-binding group and linker of the resin-bound HDAC inhibitor 3. After Fmoc-deprotection of the precursor, Fmoc-4-aminobenzoic acid was used to complete the HDACi (4). The last step before the introduction of the DCAF11 ligand was the attachment of various spacers, which was performed in the same manner as previous couplings steps to produce 5a-j. The precursors 4 and 5a-j were then used to install the DCAF11 ligand by an on resin U-4CR. To this end, 3,4-dichlorobenzaldehyde, 2-chloroacetic acid, and benzyl isocyanide were used in the U-4CR. This synthetic approach enabled the introduction of the DCAF11 ligand in one final step. Finally, all compounds were cleaved from the resin and purified by preparative HPLC to >95% purity. spacer-based compounds revealed some unexpected results: while the C5 spacer (compound 1h) did not reduce HDAC1 levels, PROTACs with both shorter and longer spacers showed a trend toward significant HDAC1 degradation. Interestingly, also the spacer-less degrader 2 demonstrated significant HDAC1 degradation. The most pronounced reduction of HDAC1 levels was detected for spacer-less PROTAC 2 (55%) and the longest C11 spacer bearing PROTAC 1j (71%). In addition, these two PROTACs were also capable of achieving significant reduction of HDAC6 protein levels, whereas all the other compounds showed no significant effects on HDAC6 protein abundance. Encouraged by the promising reductions in HDAC1 and HDAC6 levels, we further investigated the phenotypic effects of our DCAF11-recruiting PROTACs on cancer cells. Accordingly, we performed a cell viability assay on multiple myeloma MM.1S cells after treatment with the indicated compounds. The results are presented in Table . The rigid cyclic spacer-bearing PROTACs (1a, 1b) demonstrated diminished antiproliferative activity, whereas the spacer-less (2: EC50 = 1.46 µM) and the longest alkyl spacer (1j: EC50 = 2.79 µM) yielded pronounced effects.