Abstract
Fibroblast growth factor receptor (FGFR) represents an attractive oncology target for cancer therapy in view of its critical role in promoting cancer formation and progression, as well as causing resistance to approved therapies. In this article, we describe the identification of the potent pan-FGFR inhibitor (R)-21c (FGFR1-4 IC50 values of 0.9, 2.0, 2.0, and 6.1 nM, respectively). Compound (R)-21c exhibited excellent in vitro inhibitory activity against a panel of FGFR-amplified cell lines. Western blot analysis demonstrated that (R)-21c suppressed FGF/FGFR and downstream signaling pathways at nanomolar concentrations. Moreover, (R)-21c provided nearly complete inhibition of tumor growth (96.9% TGI) in NCI-H1581 (FGFR1-amplified) xenograft mice model at the dose of 10 mg/kg/qd via oral administration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Benzimidazoles / chemical synthesis
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacology*
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Cell Line, Tumor
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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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Female
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Humans
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Indazoles / chemical synthesis
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Indazoles / chemistry
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Indazoles / pharmacology*
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Mice
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Mice, Nude
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Models, Molecular
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Molecular Structure
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Neoplasms, Experimental / drug therapy
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Neoplasms, Experimental / pathology
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Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Benzimidazoles
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Indazoles
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Receptors, Fibroblast Growth Factor
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benzimidazole-5-(1-(3,5-dichloropyridin-4-yl)ethoxy)-1H-indazole