PROTAC‐Mediated HDAC7 Protein Degradation Unveils Its Deacetylase‐Independent Proinflammatory Function in Macrophages DOI Creative Commons

Kailibinuer Kadier,

Tian Niu,

Baoli Ding

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: July 25, 2024

Abstract Class IIa histone deacetylases (Class HDACs) play critical roles in regulating essential cellular metabolism and inflammatory pathways. However, dissecting the specific of each class HDAC isoform is hindered by pan‐inhibitory effect current inhibitors a lack tools to probe their functions beyond epigenetic regulation. In this study, novel PROTAC‐based compound B4 developed, which selectively targets degrades HDAC7, resulting effective attenuation set proinflammatory cytokines both lipopolysaccharide (LPS)‐stimulated macrophages mouse model. By employing as molecular probe, evidence found for previously explored role HDAC7 that surpasses its deacetylase function, suggesting broader implications processes. Mechanistic investigations reveal involvement Toll‐like receptor 4 (TLR4) signaling pathway directly interacting with TNF receptor‐associated factor 6 TGFβ‐activated kinase 1 (TRAF6‐TAK1) complex, thereby initiating activation downstream mitogen‐activated protein kinase/nuclear factor‐κB (MAPK/NF‐κB) cascade subsequent gene transcription. This study expands insight into HDAC7's within intricate networks highlights therapeutic potential target anti‐inflammatory treatments.

Language: Английский

Auto-RapTAC: A Versatile and Sustainable Platform for the Automated Rapid Synthesis and Evaluation of PROTAC DOI

Jiexuan Chen,

Mingfei Wu,

Jun Mo

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 4, 2025

The tedious synthesis and limited throughput biological evaluation remain a great challenge for discovering new proteolysis targeting chimera (PROTAC). To rapidly identify potential PROTAC lead compounds, we report platform named Auto-RapTAC. Based on the modular characteristic of molecule, streamlined workflow that integrates lab automation with "click chemistry" joint building-block libraries was constructed. This facilitates autonomous generation variety PROTACs, each distinct linkers E3 ligase ligands, all stored in biocompatible solutions. ready-for-screening (R4S) approach, when paired fluorescence-based assays, enables efficient assessment degradation activity high-throughput manner. further test capability platform, six PROTACs target CDK2, CDK12, BCL6 within mere 8-day time frame target. In all, this could find broad application not only but also rapid development novel heterobifunctional modalities.

Language: Английский

Citations

0
PROTAC‐Mediated HDAC7 Protein Degradation Unveils Its Deacetylase‐Independent Proinflammatory Function in Macrophages DOI Creative Commons

Kailibinuer Kadier,

Tian Niu,

Baoli Ding

et al.

Advanced Science, Journal Year: 2024, Volume and Issue: unknown

Published: July 25, 2024

Abstract Class IIa histone deacetylases (Class HDACs) play critical roles in regulating essential cellular metabolism and inflammatory pathways. However, dissecting the specific of each class HDAC isoform is hindered by pan‐inhibitory effect current inhibitors a lack tools to probe their functions beyond epigenetic regulation. In this study, novel PROTAC‐based compound B4 developed, which selectively targets degrades HDAC7, resulting effective attenuation set proinflammatory cytokines both lipopolysaccharide (LPS)‐stimulated macrophages mouse model. By employing as molecular probe, evidence found for previously explored role HDAC7 that surpasses its deacetylase function, suggesting broader implications processes. Mechanistic investigations reveal involvement Toll‐like receptor 4 (TLR4) signaling pathway directly interacting with TNF receptor‐associated factor 6 TGFβ‐activated kinase 1 (TRAF6‐TAK1) complex, thereby initiating activation downstream mitogen‐activated protein kinase/nuclear factor‐κB (MAPK/NF‐κB) cascade subsequent gene transcription. This study expands insight into HDAC7's within intricate networks highlights therapeutic potential target anti‐inflammatory treatments.

Language: Английский

Citations

2