Design, synthesis, and anticancer evaluation of arylurea derivatives as potent and selective type II irreversible
Min Wang1, Li Lan1, Yu-Wei Wang1
1Jiangsu Key Laboratory of Drug Design & Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
Abstract:
Aberrant FGF19/FGFR4 signaling has been demonstrated to be an oncogenic driver of growth and survival in human hepatocellular carcinoma (HCC). At present, the development of FGFR4-specific drugs has become a hotspot in tumor-targeted therapy research. However, no selective FGFR4 inhibitors have been approved by FDA so far. Currently, most of the reported FGFR4 inhibitors that use a covalent targeting strategy to be selective are typical type I inhibitors with a single type. Here, based on Ponatinib, we designed and synthesized a series of arylurea derivatives as novel type II irreversible covalent inhibitors of FGFR4. Among them, the representative compound 6v exhibited an IC50 value of 74 nM against FGFR4 and antiproliferative potency of 0.25 μM and 0.22 μM against Huh7 and Hep3B cell lines. Western blotting results showed that compound 6v significantly inhibited the phosphorylation of FGFR4 and its downstream signaling factors AKT and ERK in a dose-dependent manner in Hep3B cell. These results showed that this series of compounds, as type II irreversible FGFR4 inhibitors, are worthy of further research and structural optimization.
Insights
Researchers developed novel type II irreversible covalent inhibitors targeting FGFR4, a key driver in hepatocellular carcinoma (HCC). Compound 6v demonstrated significant anti-cancer activity, inhibiting tumor cell growth and downstream signaling pathways.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Aberrant Fibroblast Growth Factor 19 (FGF19)/Fibroblast Growth Factor Receptor 4 (FGFR4) signaling drives hepatocellular carcinoma (HCC) progression.
- Developing selective FGFR4 inhibitors is crucial for targeted HCC therapy, but none are FDA-approved.
- Existing covalent FGFR4 inhibitors are primarily type I, necessitating exploration of alternative inhibition strategies.
Purpose of the Study:
- To design and synthesize novel type II irreversible covalent inhibitors of FGFR4.
- To evaluate the efficacy of these inhibitors against HCC cell lines.
- To investigate the mechanism of action of the most potent compounds.
Main Methods:
- Structure-based drug design using Ponatinib as a scaffold.
- Synthesis of arylurea derivatives.
- In vitro assays including IC50 determination against FGFR4 and antiproliferative assays against HCC cell lines (Huh7, Hep3B).
- Western blotting to assess inhibition of FGFR4 phosphorylation and downstream signaling (AKT, ERK).
Main Results:
- A series of novel type II irreversible covalent FGFR4 inhibitors were synthesized.
- Compound 6v showed potent inhibition of FGFR4 (IC50 = 74 nM) and significant antiproliferative effects against HCC cell lines (0.25 μM in Huh7, 0.22 μM in Hep3B).
- Compound 6v effectively inhibited FGFR4 phosphorylation and downstream AKT/ERK signaling in a dose-dependent manner.
Conclusions:
- The synthesized arylurea derivatives represent a promising class of type II irreversible FGFR4 inhibitors.
- Compound 6v demonstrates significant potential for further development in HCC targeted therapy.
- These findings warrant further research and structural optimization for clinical application.
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