Development of a Potent and Specific FGFR4 Inhibitor for the Treatment of Hepatocellular Carcinoma
Renata Rezende Miranda1, Ying Fu2, Xiaojuan Chen2,3
1Department of Chemistry and Loker Hydrocarbon Research Institute, University of Southern California, Los Angeles, California 90089, United States.
Abstract:
Abnormal activation of the fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling pathway has been shown to drive the proliferation of a significant portion of hepatocellular carcinoma (HCC). Resistance and toxicity are serious drawbacks that have been observed upon use of the current first- and second-line treatment options for HCC, therefore warranting the investigation of alternative therapeutic approaches. We report the development and biological characterization of a covalent inhibitor that is highly potent and exquisitely specific to FGFR4. The crystal structure of this inhibitor in complex with FGFR4 was solved, confirming its covalent binding and revealing its binding mode. We also describe the first clickable probe for FGFR4 that can be used to directly measure target engagement in cells. Our compound exhibited great antitumor activity in HCC cell lines and tumor xenograft models. These results provide evidence of a promising therapeutic lead for the treatment of a subset of HCC patients.
Insights
A novel covalent inhibitor targeting fibroblast growth factor receptor 4 (FGFR4) shows potent antitumor activity in hepatocellular carcinoma (HCC) models. This discovery offers a promising new therapeutic strategy for HCC patients resistant to current treatments.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Abnormal fibroblast growth factor 19 (FGF19)/fibroblast growth factor receptor 4 (FGFR4) signaling drives hepatocellular carcinoma (HCC) proliferation.
- Current HCC treatments face resistance and toxicity issues, necessitating alternative therapies.
Purpose of the Study:
- To develop and characterize a potent and specific covalent inhibitor of FGFR4.
- To evaluate the therapeutic potential of this inhibitor in HCC.
Main Methods:
- Development and biological characterization of a covalent FGFR4 inhibitor.
- Crystal structure determination of the inhibitor complexed with FGFR4.
- Creation of the first clickable probe for FGFR4 target engagement measurement.
- In vitro and in vivo testing in HCC cell lines and tumor xenograft models.
Main Results:
- A highly potent and specific covalent inhibitor of FGFR4 was developed.
- The crystal structure confirmed the inhibitor's covalent binding mode to FGFR4.
- The compound demonstrated significant antitumor activity in HCC models.
- A novel clickable probe for measuring FGFR4 target engagement was created.
Conclusions:
- The developed covalent FGFR4 inhibitor is a promising therapeutic lead for a subset of HCC patients.
- This targeted approach offers a potential alternative to existing HCC treatments.
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