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

ABSTRACT: 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 e

SUBMITTER: Mahameed M 

PROVIDER: S-EPMC6443726 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature