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.
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Erschienen in
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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)
- Urheber
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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
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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14.08.2025, 10:48 MESZ
Datenpartner
Deutsche Nationalbibliothek. Bei Fragen zum Objekt wenden Sie sich bitte an den Datenpartner.
Beteiligte
- 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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