Discovery of LHQ490 as a highly selective fibroblast growth factor receptor 2 (FGFR2) inhibitor.
Eur J Med Chem
; 272: 116473, 2024 Jun 05.
Article
em En
| MEDLINE
| ID: mdl-38718625
ABSTRACT
Fibroblast growth factor receptor 2 (FGFR2) represents an appealing therapeutic target for multiple cancers, yet no selective FGFR2 inhibitors have been approved for clinical use to date. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors. The representative compound LHQ490 potently inhibited FGFR2 kinase activity with an IC50 of 5.2 nM, and was >61-, >34-, and >293-fold selective against FGFR1, FGFR3, and FGFR4, respectively. LHQ490 also exhibited high selectivity in a panel of 416 kinases. Cell-based studies revealed that LHQ490 efficiently suppressed the proliferation of BaF3-FGFR2 cells with an IC50 value of 1.4 nM, and displayed >70- and >714-fold selectivity against BaF3-FGFR1 and the parental BaF3 cells, respectively. More importantly, LHQ490 potently suppressed the FGFR2 signaling pathways, selectively inhibited FGFR2-driven cancer cell proliferation, and induced apoptosis of FGFR2-driven cancer cells. Taken together, this study provides a potent and highly selective FGFR2 inhibitor for further development of FGFR2-targeted therapeutic agents.
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MEDLINE
Assunto principal:
Inibidores de Proteínas Quinases
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Proliferação de Células
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Relação Dose-Resposta a Droga
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Receptor Tipo 2 de Fator de Crescimento de Fibroblastos
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Descoberta de Drogas
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article