Nf449 is a novel inhibitor of fibroblast growth factor receptor 3 (fgfr3) signaling active in chondrocytes and multiple myeloma cells

• Autoři: KREJČÍ Pavel; MURAKAMI Shunichi; PROCHÁZKOVÁ Jiřina; TRANTÍREK Lukáš; CHLEBOVÁ Katarína; OUYANG Zhufeng; AKLIAN Anie; SMUTNÝ Jiří; BRYJA Vítězslav; KOZUBÍK Alois; WILCOX Wiliam R.
• Rok publikování: 2010
• Druh: Článek v odborném periodiku
• Časopis / Zdroj: J. Biol. Chem.
• Fakulta / Pracoviště MU: Přírodovědecká fakulta
• Doi: http://dx.doi.org/10.1074/jbc.M109.083626
• Obor: Fyziologie
• Klíčová slova: ERK MAP KINASE; ACTIVATING MUTATIONS; PROLIFERATION; SURAMIN; PATHWAY; DIFFERENTIATION; ACHONDROPLASIA; ASSOCIATION; ANTAGONIST; EXPRESSION
• Popis: The FGFR3 receptor tyrosine kinase represents an attractive target for therapy due to its role in several human disorders, including skeletal dysplasias, multiple myeloma, and cervical and bladder carcinomas. By using molecular library screening, we identified a compound named NF449 with inhibitory activity toward FGFR3 signaling. In cultured chondrocytes and murine limb organ culture, NF449 rescued FGFR3-mediated extracellular matrix loss and growth inhibition, which represent two major cellular phenotypes of aberrant FGFR3 signaling in cartilage. Similarly, NF449 antagonized FGFR3 action in the multiple myeloma cell lines OPM2 and KMS11. In cell-free kinase assays, NF449 inhibited the kinase activity of both wild type and a disease-associated FGFR3 mutant (K650E) in a fashion that appeared non-competitive with ATP.

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