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Simultaneous Measurement of HDAC1 and HDAC6 Activity in HeLa Cells Using UHPLC-MS
Published on: August 10, 2017
Structure-based design, synthesis and in vitro antiproliferative effects studies of novel dual BRD4/HDAC inhibitors
Mingfeng Shao1, Linhong He1, Li Zheng1
1Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, Sichuan 610041, PR China.
Abstract:
Histone acetylation marks play important roles in controlling gene expressions and are removed by histone deacetylases (HDACs). These marks are read by bromodomain and extra-terminal (BET) proteins, whose targeted inhibitors are under clinical investigation. BET and HDAC inhibitors have been demonstrated to be synergistically killing in Mycinduced murine lymphoma. Herein, we combine the inhibitory activities of BET and HDAC into one molecule through structure-based design method and evaluate its function. The majority of these synthesized compounds showed inhibitory activity against second bromdomains(BRD) of BRD4 and HDAC1. Among them, 16ae presented anti-proliferative effects against human acute myelogenous leukemia (AML) cell lines in vitro, and 16ae is confirmed to reduce the expression of Myc by Western blot analysis. Those results indicated that 16ae is a potent dual BRD4/HDAC inhibitor and deserves further investigation.
Insights
Researchers developed a novel dual inhibitor targeting Bromodomain and extra-terminal (BET) proteins and Histone Deacetylases (HDACs). This compound, 16ae, shows potent anti-leukemia effects by reducing Myc expression in acute myelogenous leukemia (AML) cells.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Histone acetylation regulates gene expression and is modulated by Histone Deacetylases (HDACs).
- Bromodomain and extra-terminal (BET) proteins recognize acetylated histone marks, influencing gene transcription.
- Dual inhibition of BET and HDAC pathways shows synergistic effects in certain cancers, like Myc-induced lymphoma.
Purpose of the Study:
- To design and synthesize a single molecule combining BET and HDAC inhibitory activities.
- To evaluate the anti-proliferative potential of novel dual inhibitors against cancer cell lines.
- To investigate the mechanism of action, specifically targeting Myc expression.
Main Methods:
- Structure-based drug design was employed to create novel compounds.
- Synthesized compounds were tested for inhibitory activity against BRD4 (BET family) and HDAC1.
- In vitro anti-proliferative assays were performed on human acute myelogenous leukemia (AML) cell lines.
- Western blot analysis was used to assess Myc expression levels.
Main Results:
- Most synthesized compounds exhibited inhibitory activity against BRD4 and HDAC1.
- Compound 16ae demonstrated significant anti-proliferative effects on AML cell lines.
- 16ae was confirmed to decrease Myc protein expression.
Conclusions:
- Compound 16ae is a potent dual inhibitor of BRD4 and HDAC1.
- The findings suggest 16ae has therapeutic potential for acute myelogenous leukemia (AML).
- Further investigation of 16ae as a dual BRD4/HDAC inhibitor is warranted.
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