Discovery and Development of INCB126503: A Potent and Selective FGFR2/3 Inhibitor

Keywords

tyrosine kinases - FGFR - isoform selectivity

Significance

The fibroblast growth factor family of tyrosine kinases have emerged as attractive targets for the treatment of a variety of cancers. Three small-molecule FGFR inhibitors have been approved for the treatment of cancers associated with FGFR2 /3 genetic alterations. A challenge with these approved compounds is the unselective targeting of FGFR1 and/or FGFR4, leading to undesirable side effects including hyperphosphatemia and diarrhea. In this work, the discovery of potent and FGFR2 /3 selective inhibitor INCB126503 is disclosed. In addition to the improved selectivity profile, INCB126503 was also equipotent against gatekeeper mutants.

 

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Comment

High-throughput screening identified compound 3 with modest FGFR3 potency and selectivity over FGFR1. SAR studies of the bicyclic core led to pyrazolo[4,3-b]pyridine 5 with improved potency and selectivity. Substitution of the C5-aryl group with a 2,3-dimethylphenyl group and C6 with a methoxy group produced a substantial improvement in FGFR3 potency and selectivity. Substitution of the pyrazole ring in 5 with an aminopyridine led to substantially improved ADME properties culminating in INCB126503. Notably, INCB126503 was equipotent for FGFR3-V555 L and FGFR-V555 M gatekeeper mutants. INCB126503 showed dose-dependent tumor growth inhibition in mouse xenograft models. Additionally, INCB126503 showed no impact on phosphorus levels in naïve mice at any dose, suggesting poor inhibition of FGFR1.

 

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Publication History

Article published online:
23 July 2025