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

• Published in: Angewandte Chemie International Edition Vol. 62; no. 42; p. e202310059
• Main Authors: Zhao, Chunlong, Chen, Shipeng, Chen, Deng, Río‐Bergé, Clàudia, Zhang, Jianqiu, Van Der Wouden, Petra E., Daemen, Toos, Dekker, Frank J.
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 16-10-2023
• Edition: International ed. in English
• Subjects: Anti-inflammatory agents; Chimeras; Cytokines; Gene expression; Histone deacetylase; Histones; Inflammation; Lipopolysaccharides; Macrophages; Molecular modelling; Polarization; Proteolysis
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202310059

Macrophage polarization plays a crucial role in inflammatory processes. The histone deacetylase 3 (HDAC3) has a deacetylase‐independent function that can activate pro‐inflammatory gene expression in lipopolysaccharide‐stimulated M1‐like macrophages and cannot be blocked by traditional small‐molecule HDAC3 inhibitors. Here we employed the proteolysis targeting chimera (PROTAC) technology to target the deacetylase‐independent function of HDAC3. We developed a potent and selective HDAC3‐directed PROTAC,
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, demonstrating that this molecular mechanism can be targeted with small molecule therapeutics.