Histone Deacetylase 3‐Directed PROTACs Have Anti‐inflammatory Potential by Blocking Polarization of M0‐like into M1‐like Macrophages
Abstract: 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.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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Histone Deacetylase 3‐Directed PROTACs Have Anti‐inflammatory Potential by Blocking Polarization of M0‐like into M1‐like Macrophages ; day:08 ; month:09 ; year:2023 ; extent:12
Angewandte Chemie / International edition. International edition ; (08.09.2023) (gesamt 12)
- Creator
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Zhao, Chunlong
Chen, Shipeng
Chen, Deng
Río‐Bergé, Clàudia
Zhang, Jianqiu
Van Der Wouden, Petra E.
Daemen, Toos
Dekker, Frank J.
- DOI
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10.1002/anie.202310059
- URN
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urn:nbn:de:101:1-2023090815384916455381
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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14.08.2025, 10:48 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Zhao, Chunlong
- Chen, Shipeng
- Chen, Deng
- Río‐Bergé, Clàudia
- Zhang, Jianqiu
- Van Der Wouden, Petra E.
- Daemen, Toos
- Dekker, Frank J.
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Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells
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TLR2 stimulation impairs anti-inflammatory activity of M2-like macrophages, generating a chimeric M1/M2 phenotype
Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells
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A reduced M1-like/M2-like ratio of macrophages in healthy adipose tissue expansion during SGLT2 inhibition
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