We chose the previously published covalent E3 ligase ligand of Nomura and co-workers 34 (10, Scheme 1 and Scheme S1, Supporting Information) to hijack FEM1B and to induce proteasomal degradation of HDACs. The POI ligand was inspired by the unselective HDAC inhibitor vorinostat, in order to engage a broad spectrum of HDAC isoforms. The exit vector of the POI and E3 ligase ligands have been already established, but for the PROTAC spacers, we incorporated a variety of different types to cover a broad range of length, rigidity, and polarity. For the design of our PROTACs, we included three short and rigid cyclic spacers (1a-c), three longer and flexible polyethylene glycol (PEG) spacers (1d-f), and alkyl spacers of varying lengths in combination with high flexibility (1g-k). In addition, a spacer-less compound (2) was designed to minimize the distance between the HDAC and FEM1B ligand (Figure ). The desired PROTACs were prepared by solid-phase synthesis to enable a rapid generation of a degrader library. To this end, we followed our previously published protocol starting from a 2-chlorotrityl chloride resin (2-CTC resin, Scheme 1). In detail, the resin was first modified by the reaction with N-hydroxyphthalimide. The phthaloyl group was subsequently deprotected by treatment with hydrazine hydrate to release the immobilized hydroxylamine as a precursor of the zinc-binding group (not shown). Next, the linker of the HDAC ligand was added by the attachment of Fmoc-protected 7-aminoheptanoic acid using HATU and HOBt as reagents for the amide coupling reaction. This provided the preloaded resin 3 with a loading of 0.62 -0.68 mmol/g, serving as key building block for the subsequent parallel synthesis. After Fmoc-deprotection of the resin-bound precursor, Fmoc-protected para-aminobenzoic acid was added as the HDACi cap group by another amide coupling reaction. This sequence yielded the resin-bound, Fmoc-protected HDAC ligand 4. To generate the library of twelve PROTACs, the FEM1B ligand 10 was synthesized according to literature known protocols, with slight modification (Scheme S1, Supporting Information). In the first step, the FEM1B ligand was attached to the resin bound HDAC ligand 4 by Fmoc deprotection and amide coupling reaction. After cleavage from the resin by treatment with 5% TFA and 5% triisopropylsilane in dichloromethane, the spacer-less PROTAC 2 was generated in a yield of 39% over 5 steps and a purity of > 95% after purification by preparative HPLC. The eleven spacer-containing PROTACs were synthesized in a similar manner, with the additional step of coupling the respective Fmoc-protected spacer (5a-k) before attaching the FEM1B ligand 10. After cleavage and purification by preparative HPLC, the spacercontaining PROTACs (1a-k) were obtained with yields ranging from 9% to 45% over 7 steps.