Figure summarizes the analyzed HDAC1 and 6 levels: HDAC1 was not degraded by PROTACs bearing the cyclic spacers, but the longer and more polar PEG spacer-containing PROTACs showed a significant reduction of up to 51% (1e). The alkyl 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.