Histone Deacetylase 3-Directed PROTACs Have Anti-inflammatory Potential by Blocking Polarization of M0-like into M1-like Macrophages.

Macrophage polarization plays a crucial role in inflammatory processes. The histone deacetylase 3 (HDAC3) has deacetylase-independent function that can activate pro-inflammatory gene expression in LPS-stimulated M1-like macrophages and cannot be blocked by traditional small-molecule HDAC3 inhibitors. Here we employ the proteolysis targeting chimera (PROTAC) technology to target the deacetylase-independent function of HDAC3. We developed a potent and selective HDAC3-directed PROTAC, denoted P7, which induces nearly complete HDAC3 degradation at low micromolar concentrations in both THP-1 cells and human primary macrophages. P7 increases the anti-inflammatory cytokine secretion in THP-1 derived M1-like macrophages. Importantly, P7 decreases the secretion of pro-inflammatory cytokines in M1-like macrophages derived from human primary macrophages. This can be explained by the observed inhibition of macrophage polarization from M0-like into M1-like macrophage. In conclusion, we demonstrate that the HDAC3-directed PROTAC P7 has anti-inflammatory activity and blocks macrophage polarization, which demonstrates that this molecular mechanism can be targeted with small molecule therapeutics.