Abstract
Aberrant activation of FGFR has been linked to the pathogenesis of many tumor types. Selective inhibition of FGFR has emerged as a promising approach for cancer treatment. Herein, we describe the discovery of compound 38 (INCB054828, pemigatinib), a highly potent and selective inhibitor of FGFR1, FGFR2, and FGFR3 with excellent physiochemical properties and pharmacokinetic profiles. Pemigatinib has received accelerated approval from the U.S. Food and Drug Administration for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement. Additional clinical trials are ongoing to evaluate pemigatinib in patients with FGFR alterations.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Dose-Response Relationship, Drug
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Drug Discovery*
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Humans
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Molecular Structure
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Morpholines / chemical synthesis
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Morpholines / chemistry
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Morpholines / pharmacology*
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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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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Pyrroles / chemical synthesis
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors*
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Receptor, Fibroblast Growth Factor, Type 1 / metabolism
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Receptor, Fibroblast Growth Factor, Type 2 / antagonists & inhibitors*
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Receptor, Fibroblast Growth Factor, Type 2 / metabolism
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Receptor, Fibroblast Growth Factor, Type 3 / antagonists & inhibitors*
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Receptor, Fibroblast Growth Factor, Type 3 / metabolism
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Structure-Activity Relationship
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United States
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United States Food and Drug Administration
Substances
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Morpholines
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Protein Kinase Inhibitors
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Pyrimidines
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Pyrroles
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FGFR1 protein, human
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FGFR2 protein, human
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FGFR3 protein, human
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Receptor, Fibroblast Growth Factor, Type 1
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Receptor, Fibroblast Growth Factor, Type 2
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Receptor, Fibroblast Growth Factor, Type 3
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pemigatinib