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
Identifikátory výsledku
Kód výsledku v IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F16%3A00063390" target="_blank" >RIV/00159816:_____/16:00063390 - isvavai.cz</a>
Nalezeny alternativní kódy
RIV/68081707:_____/16:00458514 RIV/67985904:_____/16:00458514 RIV/00216224:14110/16:00089183 RIV/62157124:16170/16:43874169
Výsledek na webu
<a href="http://dx.doi.org/10.1093/hmg/ddv441" target="_blank" >http://dx.doi.org/10.1093/hmg/ddv441</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1093/hmg/ddv441" target="_blank" >10.1093/hmg/ddv441</a>
Alternativní jazyky
Jazyk výsledku
angličtina
Název v původním jazyce
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
Popis výsledku v původním jazyce
Activating mutations in the FGFR3 cause the most common genetic form of human dwarfism, achondroplasia. Small chemical inhibitors of FGFR tyrosine kinase activity (TKI) are considered to be viable option for treating achondroplasia but little experimental evidence supports this claim. We evaluated five FGFR 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 compromises their use for treatment of achondroplasia. Conceptually different avenues of therapeutic FGFR3 targeting should be investigated.
Název v anglickém jazyce
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
Popis výsledku anglicky
Activating mutations in the FGFR3 cause the most common genetic form of human dwarfism, achondroplasia. Small chemical inhibitors of FGFR tyrosine kinase activity (TKI) are considered to be viable option for treating achondroplasia but little experimental evidence supports this claim. We evaluated five FGFR 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 compromises their use for treatment of achondroplasia. Conceptually different avenues of therapeutic FGFR3 targeting should be investigated.
Klasifikace
Druh
J<sub>x</sub> - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)
CEP obor
EB - Genetika a molekulární biologie
OECD FORD obor
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Návaznosti výsledku
Projekt
Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.
Návaznosti
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Ostatní
Rok uplatnění
2016
Kód důvěrnosti údajů
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Údaje specifické pro druh výsledku
Název periodika
Human Molecular Genetics
ISSN
0964-6906
e-ISSN
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Svazek periodika
25
Číslo periodika v rámci svazku
1
Stát vydavatele periodika
GB - Spojené království Velké Británie a Severního Irska
Počet stran výsledku
24
Strana od-do
9-23
Kód UT WoS článku
000372147800002
EID výsledku v databázi Scopus
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