Solid-phase synthesis of cereblon-recruiting selective histone deacetylase 6 degraders (HDAC6 PROTACs) with anti-leukemic activity

Selective histone deacetylase 6 (HDAC6) inhibitors are useful tools to study the function of the second catalytic domain of HDAC6, but they cannot interfere with (non)-enzymatic functions of HDAC6, which are mediated via the first catalytic domain or the ubiquitin binding domain. In this work, we utilized the proteolysis targeting chimera (PROTAC) technology to achieve the chemical knock-down of HDAC6. Two series of cereblon-recruiting PROTACs were synthesized via a solid-phase parallel synthesis approach, which allowed the rapid preparation of two HDAC6 degrader mini libraries. The PROTACs were either based on an unselective vorinostat-like HDAC ligand or derived from a selective HDAC6 inhibitor. Notably, both PROTAC series demonstrated selective degradation of HDAC6 in leukemia cell lines. The best degraders from each series (denoted A6 and B4) were capable of degrading HDAC6 via ternary complex formation and the ubiquitin−proteasome pathway, with DC50 values of 3.7 and 13.3 nM, respectively. Moreover, HDAC6 degradation of A6 and intracellular (nucleocytoplasmic) localization of a fluorescein-labelled PROTAC (A7) was determined by fluorescence microscopy. PROTAC A6 demonstrated promising antiproliferative activity via inducing apoptosis in myeloid leukemia cell lines. These findings highlight the potential of this series of degraders as effective pharmacological tools for the targeted degradation of HDAC6.