Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes
Language English Country Great Britain, England Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
26494904
DOI
10.1093/hmg/ddv441
PII: ddv441
Knihovny.cz E-resources
- MeSH
- Achondroplasia drug therapy MeSH
- Benzamides pharmacology MeSH
- Chondrocytes metabolism MeSH
- Cartilage drug effects metabolism MeSH
- Phenylurea Compounds pharmacology MeSH
- Catalysis drug effects MeSH
- Cells, Cultured MeSH
- Chick Embryo MeSH
- Humans MeSH
- Mice MeSH
- Piperazines pharmacology MeSH
- Pyrazoles pharmacology MeSH
- Pyrimidines pharmacology MeSH
- Pyrroles pharmacology MeSH
- Receptors, Fibroblast Growth Factor antagonists & inhibitors MeSH
- Signal Transduction drug effects MeSH
- Syndrome MeSH
- Receptor Protein-Tyrosine Kinases antagonists & inhibitors MeSH
- Animals MeSH
- Check Tag
- Chick Embryo MeSH
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- AZD 1480 MeSH Browser
- AZD4547 MeSH Browser
- Benzamides MeSH
- Phenylurea Compounds MeSH
- infigratinib MeSH Browser
- PD 173074 MeSH Browser
- Piperazines MeSH
- Pyrazoles MeSH
- Pyrimidines MeSH
- Pyrroles MeSH
- Receptors, Fibroblast Growth Factor MeSH
- SU 5402 MeSH Browser
- Receptor Protein-Tyrosine Kinases MeSH
Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) cause the most common genetic form of human dwarfism, achondroplasia (ACH). Small chemical inhibitors of FGFR tyrosine kinase activity are considered to be viable option for treating ACH, but little experimental evidence supports this claim. We evaluated five FGFR tyrosine kinase inhibitors (TKIs) (SU5402, PD173074, AZD1480, AZD4547 and BGJ398) for their activity against FGFR signaling in chondrocytes. All five TKIs strongly inhibited FGFR activation in cultured chondrocytes and limb rudiment cultures, completely relieving FGFR-mediated inhibition of chondrocyte proliferation and maturation. In contrast, TKI treatment of newborn mice did not improve skeletal growth and had lethal toxic effects on the liver, lungs and kidneys. In cell-free kinase assays as well as in vitro and in vivo cell assays, none of the tested TKIs demonstrated selectivity for FGFR3 over three other FGFR tyrosine kinases. In addition, the TKIs exhibited significant off-target activity when screened against a panel of 14 unrelated tyrosine kinases. This was most extensive in SU5402 and AZD1480, which inhibited DDR2, IGF1R, FLT3, TRKA, FLT4, ABL and JAK3 with efficiencies similar to or greater than those for FGFR. Low target specificity and toxicity of FGFR TKIs thus compromise their use for treatment of ACH. Conceptually, different avenues of therapeutic FGFR3 targeting should be investigated.
Department of Biology Faculty of Medicine Masaryk University Brno Czech Republic
Department of Clinical Biochemistry University Hospital Olomouc Czech Republic
Institute of Experimental Biology Faculty of Sciences Masaryk University Brno Czech Republic
References provided by Crossref.org
Inhibitor repurposing reveals ALK, LTK, FGFR, RET and TRK kinases as the targets of AZD1480
