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Histone Deacetylase 3-Directed PROTACs Have Anti-inflammatory Potential by Blocking Polarization of M0-like into
Chunlong Zhao1, Shipeng Chen2, Deng Chen1
1Department of Chemical and Pharmaceutical Biology, Groningen, Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
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.
Insights
Researchers developed a novel PROTAC molecule, P7, to target histone deacetylase 3 (HDAC3). P7 effectively degrades HDAC3, reducing pro-inflammatory responses and inhibiting macrophage polarization, offering a new therapeutic avenue.
Area of Science:
- Immunology
- Molecular Biology
- Drug Discovery
Background:
- Macrophage polarization is central to inflammation.
- Histone deacetylase 3 (HDAC3) has a deacetylase-independent function promoting pro-inflammatory gene expression.
- This function is resistant to conventional HDAC3 inhibitors.
Purpose of the Study:
- To utilize proteolysis targeting chimera (PROTAC) technology to target the deacetylase-independent function of HDAC3.
- To develop a novel therapeutic agent for modulating macrophage polarization and inflammatory responses.
Main Methods:
- Development of a selective HDAC3-directed PROTAC, named P7.
- Assessment of P7's efficacy in degrading HDAC3 in THP-1 cells and human primary macrophages.
- Evaluation of P7's impact on cytokine secretion and macrophage polarization (M0 to M1).
Main Results:
- P7 achieved near-complete HDAC3 degradation at low micromolar concentrations.
- P7 enhanced anti-inflammatory cytokine secretion in THP-1 derived macrophages.
- P7 significantly decreased pro-inflammatory cytokine secretion in human primary macrophages by inhibiting M1 polarization.
Conclusions:
- The HDAC3-directed PROTAC P7 exhibits significant anti-inflammatory activity.
- P7 effectively blocks pro-inflammatory macrophage polarization.
- This study validates targeting the deacetylase-independent function of HDAC3 with small molecule therapeutics like PROTACs.
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