Research Papers:

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

Iva Gudernova, Lukas Balek, Miroslav Varecha, Jana Fialova Kucerova, Michaela Kunova Bosakova, Bohumil Fafilek, Veronika Palusova, Stjepan Uldrijan, Lukas Trantirek and Pavel Krejci _

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Oncotarget. 2017; 8:109319-109331. https://doi.org/10.18632/oncotarget.22674

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Iva Gudernova1, Lukas Balek1, Miroslav Varecha1,2, Jana Fialova Kucerova1, Michaela Kunova Bosakova1, Bohumil Fafilek1,2, Veronika Palusova1, Stjepan Uldrijan1,2, Lukas Trantirek3 and Pavel Krejci1,2

1Department of Biology, Faculty of Medicine, 62500 Brno, Czech Republic

2International Clinical Research Center, St. Anne’s University Hospital, 65691 Brno, Czech Republic

3Central European Institute of Technology, Masaryk University, 62500 Brno, Czech Republic

Correspondence to:

Pavel Krejci, email: [email protected]

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

Received: August 01, 2017    Accepted: October 28, 2017    Published: November 27, 2017


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.

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