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The unfolded protein response modulators GSK2606414 and KIRA6 are potent KIT inhibitors

Journal article
Authors M. Mahameed
T. Wilhelm
O. Darawshi
A. Obiedat
W. S. Tommy
C. Chintha
T. Schubert
A. Samali
E. Chevet
Leif A Eriksson
M. Huber
B. Tirosh
Published in Cell Death and Disease
Volume 10
Issue 4
ISSN 2041-4889
Publication year 2019
Published at Department of Chemistry and Molecular Biology
Language en
Keywords adenosine triphosphate, gsk 2606414, kira 6, protein kinase, protein kinase R like endoplasmic reticulum kinase, protein tyrosine kinase inhibitor, unclassified drug, Article, binding assay, cell culture, computer model, concentration response, controlled study, cytoplasm, dissociation constant, drug binding site, molecular docking, priority journal, protein domain, unfolded protein response
Subject categories Molecular biology


IRE1, PERK, and ATF6 are the three transducers of the mammalian canonical unfolded protein response (UPR). GSK2606414 is a potent inhibitor of PERK, while KIRA6 inhibits the kinase activity of IRE1. Both molecules are frequently used to probe the biological roles of the UPR in mammalian cells. In a direct binding assay, GSK2606414 bound to the cytoplasmic domain of KIT with dissociation constants (K d ) value of 664 ± 294 nM whereas KIRA6 showed a K d value of 10.8 ± 2.9 µM. In silico docking studies confirmed a compact interaction of GSK2606414 and KIRA6 with KIT ATP binding pocket. In cultured cells, GSK2606414 inhibited KIT tyrosine kinase activity at nanomolar concentrations and in a PERK-independent manner. Moreover, in contrast to other KIT inhibitors, GSK2606414 enhanced KIT endocytosis and its lysosomal degradation. Although KIRA6 also inhibited KIT at nanomolar concentrations, it did not prompt KIT degradation, and rescued KIT from GSK2606414-mediated degradation. Consistent with KIT inhibition, nanomolar concentrations of GSK2606414 and KIRA6 were sufficient to induce cell death in a KIT signaling-dependent mast cell leukemia cell line. Our data show for the first time that KIT is a shared target for two seemingly unrelated UPR inhibitors at concentrations that overlap with PERK and IRE1 inhibition. Furthermore, these data underscore discrepancies between in vitro binding measurements of kinase inhibitors and inhibition of the tyrosine kinase receptors in living cells. © 2019, The Author(s).

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