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

J 2016

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

GUDERNOVÁ, Iva, Iva VESELA, Lukáš BÁLEK, marcela BUCHTOVÁ, Hana DOSEDELOVA et. al.

Základní údaje

Originální název

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

Autoři

GUDERNOVÁ, Iva (203 Česká republika, domácí), Iva VESELA (203 Česká republika), Lukáš BÁLEK (203 Česká republika, domácí), marcela BUCHTOVÁ (203 Česká republika, domácí), Hana DOSEDELOVA (203 Česká republika), Michaela KUNOVÁ (203 Česká republika, domácí), Jakub PIVNIČKA (203 Česká republika, domácí), Iva JELÍNKOVÁ (203 Česká republika, domácí), Lucie ROUBALOVA (203 Česká republika), Alois KOZUBÍK (203 Česká republika, domácí) a Pavel KREJČÍ (203 Česká republika, domácí)

Vydání

Human Molecular Genetics, Oxford, Oxford University Press, 2016, 0964-6906

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

Genetika a molekulární biologie

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Impakt faktor

Impact factor: 5.340

Kód RIV

RIV/00216224:14110/16:00089183

Organizační jednotka

Lékařská fakulta

DOI

http://dx.doi.org/10.1093/hmg/ddv441

UT WoS

000372147800002

Klíčová slova anglicky

TYROSINE KINASE DOMAIN; ERK MAP KINASE; SELECTIVE INHIBITOR; CHONDROCYTE DIFFERENTIATION

Štítky

EL OK, podil

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 4. 8. 2016 11:03, Ing. Mgr. Věra Pospíšilíková

Anotace

V originále

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.

Návaznosti

ED3.1.00/14.0324, projekt VaV

Název: Nové biotechnologie pro medicínu

EE2.3.30.0009, projekt VaV

Název: Zaměstnáním čerstvých absolventů doktorského studia k vědecké excelenci

LH12004, projekt VaV

Název: FGFR3-specifický adaptérom a jeho role v patologické FGFR3 signalizaci v nemoci (Akronym: AMVIS-FGFR3)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, FGFR3-specifický adaptérom a jeho role v patologické FGFR3 signalizaci v nemoci

MUNI/M/0071/2013, interní kód MU

Název: High-throughput screening of compound libraries aimed on discovery of novel inhibitors of the FGFR/ERK MAP kinase signaling (Akronym: HTS-FGFR)

Investor: Masarykova univerzita, High-throughput screening of compound libraries aimed on discovery of novel inhibitors of the FGFR/ERK MAP kinase signaling, INTERDISCIPLINARY - Mezioborové výzkumné projekty

Citovat

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. Human Molecular Genetics. Oxford: Oxford University Press, 2016, roč. 25, č. 1, s. 9-23. ISSN 0964-6906. Dostupné z: https://dx.doi.org/10.1093/hmg/ddv441.

@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, 2016, roč.~25, č.~1, s.~9-23. ISSN~0964-6906. Dostupné z: https://dx.doi.org/10.1093/hmg/ddv441.

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