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

Result code in 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>

Alternative codes found

RIV/68081707:_____/16:00458514 RIV/67985904:_____/16:00458514 RIV/00216224:14110/16:00089183 RIV/62157124:16170/16:43874169

Result on the web

<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>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_x - Unclassified - Peer-reviewed scientific article (Jimp, Jsc and Jost)

CEP classification

EB - Genetics and molecular biology

OECD FORD branch

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Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2016

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Human Molecular Genetics

ISSN

0964-6906

e-ISSN

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Volume of the periodical

25

Issue of the periodical within the volume

1

Country of publishing house

GB - UNITED KINGDOM

Number of pages

24

Pages from-to

9-23

UT code for WoS article

000372147800002

EID of the result in the Scopus database

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