Expanding the range of ligandable E3 ligases for use in PROTACs is a recent development in TPD. For example, E3 ligases such as RNF4, RNF114, 31 DCAF11, 32 DCAF16, and FEM1B were successfully hijacked for TPD in recent years. All mentioned E3 ligases were targeted by covalent ligands, typically containing electrophilic groups (primarily chloroacetic acid residues), which engage specific cysteine residues of the E3 ligase. Subsequently, the ternary complex transitions into a pseudo-binary complex in which the covalently bound PROTAC-E3 ligase complex only needs to recruit the next POI for polyubiquitination (Figure , right). The FEM1B ligand EN106 (Figure ) was discovered by the Nomura group through a competitive fluorescence polarization assay. Subsequent liquid-chromatography-tandem mass spectrometry experiments confirmed that EN106 forms adducts exclusively with C186, a residue located in a region that is critical for FEM1B´s substrate recognition. This ligand was then transformed into PROTACs capable of targeting and degrading BRD4 or BCR-ABL/c-ABL. The aim of this study is to functionalize the FEM1B ligand EN106 for targeted degradation of HDACs, thereby expanding the range of E3 ligases employed for HDAC degradation. To this end, a set of twelve PROTACs was synthesized using the FDA-approved, unselective HDAC inhibitor vorinostat as a template for the POI ligand, with the goal of targeting a broad spectrum of HDACs. The synthesis of the FEM1B-recruiting degraders was realized on solid-phase, to benefit from the typically good yields and the parallel synthesis approach of solid-phase synthesis. All synthesized compounds were subsequently examined for their degradation efficacy and cytotoxicity. A detailed biological investigation of the most active compounds uncovered notable changes in the HDAC degradation selectivity profile and led to the identification of the PROTAC 1g, which demonstrated substantial anticancer properties.