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@article{1318543,
author = {Gudernová, Iva and Vesela, Iva and Bálek, Lukáš and Buchtová, marcela and Dosedelova, Hana and Kunová, Michaela and Pivnička, Jakub and Jelínková, Iva and Roubalova, Lucie and Kozubík, Alois and Krejčí, Pavel},
article_location = {Oxford},
article_number = {1},
doi = {http://dx.doi.org/10.1093/hmg/ddv441},
keywords = {TYROSINE KINASE DOMAIN; ERK MAP KINASE; SELECTIVE INHIBITOR; CHONDROCYTE DIFFERENTIATION},
language = {eng},
issn = {0964-6906},
journal = {Human Molecular Genetics},
title = {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},
volume = {25},
year = {2016}
}
TY - JOUR
ID - 1318543
AU - Gudernová, Iva - Vesela, Iva - Bálek, Lukáš - Buchtová, marcela - Dosedelova, Hana - Kunová, Michaela - Pivnička, Jakub - Jelínková, Iva - Roubalova, Lucie - Kozubík, Alois - Krejčí, Pavel
PY - 2016
TI - 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
JF - Human Molecular Genetics
VL - 25
IS - 1
SP - 9-23
EP - 9-23
PB - Oxford University Press
SN - 09646906
KW - TYROSINE KINASE DOMAIN
KW - ERK MAP KINASE
KW - SELECTIVE INHIBITOR
KW - CHONDROCYTE DIFFERENTIATION
N2 - 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.
ER -
GUDERNOVÁ, Iva, Iva VESELA, Lukáš BÁLEK, marcela BUCHTOVÁ, Hana DOSEDELOVA, Michaela KUNOVÁ, Jakub PIVNIČKA, Iva JELÍNKOVÁ, Lucie ROUBALOVA, Alois KOZUBÍK a Pavel KREJČÍ. 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. \textit{Human Molecular Genetics}. Oxford: Oxford University Press, roč.~25, č.~1, s.~9-23. ISSN~0964-6906. doi:10.1093/hmg/ddv441. 2016.
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