Inhibitor repurposing reveals ALK, LTK, FGFR, RET and TRK
kinases as the targets of AZD1480

J 2017

Inhibitor repurposing reveals ALK, LTK, FGFR, RET and TRK kinases as the targets of AZD1480

GUDERNOVÁ, Iva, Lukáš BÁLEK, Miroslav VAŘECHA, Jana FIALOVÁ KUČEROVÁ, Michaela BOSÁKOVÁ et. al.

Basic information

Original name

Inhibitor repurposing reveals ALK, LTK, FGFR, RET and TRK kinases as the targets of AZD1480

Authors

GUDERNOVÁ, Iva (203 Czech Republic, belonging to the institution), Lukáš BÁLEK (203 Czech Republic, belonging to the institution), Miroslav VAŘECHA (203 Czech Republic, belonging to the institution), Jana FIALOVÁ KUČEROVÁ (203 Czech Republic, belonging to the institution), Michaela BOSÁKOVÁ (203 Czech Republic, belonging to the institution), Bohumil FAFÍLEK (203 Czech Republic, belonging to the institution), Veronika PALUŠOVÁ (703 Slovakia, belonging to the institution), Stjepan ULDRIJAN (203 Czech Republic, belonging to the institution), Lukáš TRANTÍREK (203 Czech Republic, belonging to the institution) and Pavel KREJČÍ (203 Czech Republic, guarantor, belonging to the institution)

Edition

Oncotarget, New York, Impact Journals LLC, 2017, 1949-2553

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=22674&pubmed-linkout=1

Impact factor

Impact factor: 5.168 in 2016

RIV identification code

RIV/00216224:14110/17:00095429

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.18632/oncotarget.22674

UT WoS

000419565400082

Keywords in English

AZD1480; drug repurposing; in-cell profiling; inhibitor; receptor tyrosine kinase

Abstract

V originále

Many tyrosine kinase inhibitors (TKIs) have failed to reach human use due to insufficient activity in clinical trials. However, the failed TKIs may still benefit patients if their other kinase targets are identified by providing treatment focused on syndromes driven by these kinases. Here, we searched for novel targets of AZD1480, an inhibitor of JAK2 kinase that recently failed phase two cancer clinical trials due to a lack of activity. Twenty seven human receptor tyrosine kinases (RTKs) and 153 of their disease-associated mutants were in-cell profiled for activity in the presence of AZD1480 using a newly developed RTK plasmid library. We demonstrate that AZD1480 inhibits ALK, LTK, FGFR1-3, RET and TRKA-C kinases and uncover a physical basis of this specificity. The RTK activity profiling described here facilitates inhibitor repurposing by enabling rapid and efficient identification of novel TKI targets in cells.

Links

GA17-09525S, research and development project

Name: Neobvyklé signální dráhy lidských receptorových tyrozinových kináz

Investor: Czech Science Foundation

LH15231, research and development project

Name: Nové mechanismy vzniku fatálních kostních ciliopatií u člověka

Investor: Ministry of Education, Youth and Sports of the CR

LQ1601, research and development project

Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

NV15-33232A, research and development project

Name: Identifikace nových možností léčby achondroplásie prostřednictvím analýzy interakce FGFR3 a adaptérového proteinu Frs2

NV15-34405A, research and development project

Name: Identifikace nových možností léčby chronické myeloidní leukémie pomocí systematické analýzy interaktomu proteinu BCR-ABL

Citovat

GUDERNOVÁ, Iva, Lukáš BÁLEK, Miroslav VAŘECHA, Jana FIALOVÁ KUČEROVÁ, Michaela BOSÁKOVÁ, Bohumil FAFÍLEK, Veronika PALUŠOVÁ, Stjepan ULDRIJAN, Lukáš TRANTÍREK and Pavel KREJČÍ. Inhibitor repurposing reveals ALK, LTK, FGFR, RET and TRK kinases as the targets of AZD1480. Oncotarget. New York: Impact Journals LLC, 2017, vol. 8, No 65, p. 109319-109331. ISSN 1949-2553. Available from: https://dx.doi.org/10.18632/oncotarget.22674.

@article{1404487,
   author = {Gudernová, Iva and Bálek, Lukáš and Vařecha, Miroslav and Fialová Kučerová, Jana and Bosáková, Michaela and Fafílek, Bohumil and Palušová, Veronika and Uldrijan, Stjepan and Trantírek, Lukáš and Krejčí, Pavel},
   article_location = {New York},
   article_number = {65},
   doi = {http://dx.doi.org/10.18632/oncotarget.22674},
   keywords = {AZD1480; drug repurposing; in-cell profiling; inhibitor; receptor tyrosine kinase},
   language = {eng},
   issn = {1949-2553},
   journal = {Oncotarget},
   title = {Inhibitor repurposing reveals ALK, LTK, FGFR, RET and TRK kinases as the targets of AZD1480},
   url = {http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=22674&pubmed-linkout=1},
   volume = {8},
   year = {2017}
}

TY  - JOUR
ID  - 1404487
AU  - Gudernová, Iva - Bálek, Lukáš - Vařecha, Miroslav - Fialová Kučerová, Jana - Bosáková, Michaela - Fafílek, Bohumil - Palušová, Veronika - Uldrijan, Stjepan - Trantírek, Lukáš - Krejčí, Pavel
PY  - 2017
TI  - Inhibitor repurposing reveals ALK, LTK, FGFR, RET and TRK kinases as the targets of AZD1480
JF  - Oncotarget
VL  - 8
IS  - 65
SP  - 109319-109331
EP  - 109319-109331
PB  - Impact Journals LLC
SN  - 19492553
KW  - AZD1480
KW  - drug repurposing
KW  - in-cell profiling
KW  - inhibitor
KW  - receptor tyrosine kinase
UR  - http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=22674&pubmed-linkout=1
L2  - http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path[]=22674&pubmed-linkout=1
N2  - Many tyrosine kinase inhibitors (TKIs) have failed to reach human use due to insufficient activity in clinical trials. However, the failed TKIs may still benefit patients if their other kinase targets are identified by providing treatment focused on syndromes driven by these kinases. Here, we searched for novel targets of AZD1480, an inhibitor of JAK2 kinase that recently failed phase two cancer clinical trials due to a lack of activity. Twenty seven human receptor tyrosine kinases (RTKs) and 153 of their disease-associated mutants were in-cell profiled for activity in the presence of AZD1480 using a newly developed RTK plasmid library. We demonstrate that AZD1480 inhibits ALK, LTK, FGFR1-3, RET and TRKA-C kinases and uncover a physical basis of this specificity. The RTK activity profiling described here facilitates inhibitor repurposing by enabling rapid and efficient identification of novel TKI targets in cells.
ER  -

GUDERNOVÁ, Iva, Lukáš BÁLEK, Miroslav VAŘECHA, Jana FIALOVÁ KUČEROVÁ, Michaela BOSÁKOVÁ, Bohumil FAFÍLEK, Veronika PALUŠOVÁ, Stjepan ULDRIJAN, Lukáš TRANTÍREK and Pavel KREJČÍ. Inhibitor repurposing reveals ALK, LTK, FGFR, RET and TRK kinases as the targets of AZD1480. \textit{Oncotarget}. New York: Impact Journals LLC, 2017, vol.~8, No~65, p.~109319-109331. ISSN~1949-2553. Available from: https://dx.doi.org/10.18632/oncotarget.22674.

Detailed Information on Publication Record