Solid-Phase Synthesis of Cereblon-Recruiting Selective Histone Deacetylase 6 Degraders (HDAC6 PROTACs) with Antileukemic Activity

In this work, we utilized the proteolysis targeting chimera (PROTAC) technology to achieve the chemical knockdown of histone deacetylase 6 (HDAC6). Two series of cereblonrecruiting 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 3.5 and 19.4 nM, respectively. 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.

Automated summary

In this study, we achieved the chemical knockdown of histone deacetylase 6 (HDAC6) using proteolysis targeting chimera (PROTAC) technology. Two series of cereblon-recruiting PROTACs were synthesized, allowing the rapid preparation of HDAC6 degrader mini libraries. Both PROTAC series demonstrated selective degradation of HDAC6 in leukemia cell lines.