Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. FGFR4 has been implicated in HCC progression, making it a promising therapeutic target. We introduce an approach for identifying novel FGFR4 inhibitors by sequentially adding fragments to a common warhead unit. This strategy resulted in the discovery of a potent inhibitor, 4c, with an IC50 of 33 nM and high selectivity among members of the FGFR family. Although further optimisation is required, our approach demonstrated the potential for discovering potent FGFR4 inhibitors for HCC treatment, and provides a useful method for obtaining hit compounds from small fragments.
Keywords:
FGFR4; fragment; hit identification; kinase inhibitor; small molecule.
MeSH terms
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Carcinoma, Hepatocellular / drug therapy
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / pathology
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Cell Proliferation / drug effects
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Dose-Response Relationship, Drug*
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Drug Discovery*
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Drug Screening Assays, Antitumor
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Humans
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Molecular Structure
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Receptor, Fibroblast Growth Factor, Type 4* / antagonists & inhibitors
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Receptor, Fibroblast Growth Factor, Type 4* / metabolism
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Structure-Activity Relationship
Substances
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Receptor, Fibroblast Growth Factor, Type 4
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FGFR4 protein, human
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Protein Kinase Inhibitors
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Antineoplastic Agents
Grants and funding
This research was supported by the National Research Foundation of Korea (NRF) Grant funded by the Korean Government [2022R1A2C2010824].