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NF449 is a novel inhibitor of fibroblast growth factor receptor 3 (FGFR3) signaling active in chondrocytes and multiple myeloma cells
Author(s) -
Chlebova Katarina,
Krejci Pavel
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.620.7
Subject(s) - fibroblast growth factor receptor 3 , mapk/erk pathway , microbiology and biotechnology , signal transduction , cancer research , biology , tyrosine kinase , fibroblast growth factor receptor , kinase , receptor tyrosine kinase , fibroblast growth factor , chemistry , receptor , biochemistry
FGFR3 receptor tyrosine kinase represents an attractive target for therapy due to its candidate role in several human disorders including skeletal dysplasia, multiple myeloma, and cervical and bladder carcinomas. By using molecular library screening, we identified a compound named NF449 based on its inhibitory activity towards FGFR3 signaling in cells. In cultured chondrocytes or murine limb explants, NF449 rescued FGFR3‐mediated extracellular matrix loss and/or growth inhibition, which represent the two major cellular phenotypes of aberrant FGFR3 signaling in cartilage. Similarly, NF449 antagonized FGFR3 action in the multiple myeloma cell lines OPM2 and KMS11, as evidenced by NF449‐mediated reversal of ERK MAP kinase activation and transcript accumulation of CCL3 and CCL4 chemokines, both of which are induced by FGFR3 activation. In a cell‐free kinase assays, NF449 inhibited kinase activity of both wild‐type and disease‐associated FGFR3 mutant (K650E), in a fashion that appeared non‐competitive with ATP. Our data identify NF449 as a novel antagonist of FGFR3 signaling, applicable for FGFR3 inhibition alone or in combination with inhibitors that target the ATP binding site.