Discovery of pomalidomide-based PROTACs for selective degradation of histone deacetylase 8

Overexpression of histone deacetylase 8 (HDAC8) is associated with various diseases such as cancer. Thus, compounds that can modulate HDAC8 levels have therapeutic potential for these diseases. Based on the proteolysis targeting chimera (PROTAC) strategy, we designed and synthesized a series of HDAC8 degraders by tethering an HDAC6/8 dual inhibitor with pomalidomide (a cereblon ligand). Among them, compound ZQ-23 exhibited significant and selective degradation of HDAC8 with DC₅₀ of 147 nM and D_max of 93%, and exhibited no effects on HDAC1 and HDAC3. Interestingly, we found that the degradation of target protein started at ∼2 h after treatment with ZQ-23 and the maximal degradation effect was achieved at 10 h. The HDAC8 level was partially recovered within 24 h. In addition, ZQ-23 had no degrading effects on HDAC1 and HDAC3 at all concentrations, but could dose-dependently increase the levels of acetylated SMC-3 (HDAC8 substrate). Mechanism study demonstrated that ZQ-23 degraded HDAC8 through the ubiquitin-protease pathway, rather than lysosome system. Collectively, these results suggest that ZQ-23 represents a novel PROTAC-based HDAC8 degrader worthy of further investigation.