NF449 Is a Novel Inhibitor of Fibroblast Growth Factor Receptor 3 (FGFR3) Signaling Active in Chondrocytes and Multiple Myeloma Cells
Autor: | Jiri Smutny, Pavel Krejci, Jirina Prochazkova, Katarina Chlebova, Lukáš Trantírek, William R. Wilcox, Shunichi Murakami, Zhufeng Ouyang, Anie Aklian, Vitezslav Bryja, Alois Kozubík |
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Rok vydání: | 2010 |
Předmět: |
NF449
Chemokine Uterine Cervical Neoplasms Receptor Tyrosine Kinase Biochemistry Receptor tyrosine kinase Mice chemistry.chemical_compound 0302 clinical medicine Cricetinae RNA Neoplasm Enzyme Inhibitors 0303 health sciences biology Reverse Transcriptase Polymerase Chain Reaction Sulfates Kinase Benzenesulfonates musculoskeletal system 030220 oncology & carcinogenesis MAP Kinases (MAPKs) Female Growth inhibition Multiple Myeloma Signal Transduction musculoskeletal diseases congenital hereditary and neonatal diseases and abnormalities CHO Cells Bone and Bones 03 medical and health sciences Chondrocytes Cricetulus Growth Factors Cell Line Tumor Animals Humans Receptor Fibroblast Growth Factor Type 3 Kinase activity Molecular Biology 030304 developmental biology Wild type Cell Biology Fibroblast growth factor receptor 3 Chondrocyte stomatognathic diseases Urinary Bladder Neoplasms chemistry FGFR3 Cell culture biology.protein Cancer research Fibroblast Growth Factor Receptor RNA Protein Kinases |
Zdroj: | Journal of Biological Chemistry, 285(27), 20644. American Society for Biochemistry and Molecular Biology Inc. |
ISSN: | 0021-9258 |
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 towards 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, 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 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 noncompetitive with ATP. Our data identify NF449 as a novel antagonist of FGFR3 signaling, useful for FGFR3 inhibition alone or in combination with inhibitors that target the ATP binding site |
Databáze: | OpenAIRE |
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