Fig. 8: Diverse kinase inhibitors activating GCN2 kinase increase its affinity for ATP.
From: Activation of the integrated stress response by inhibitors of its kinases
aāf In vitro kinase reactions with 7.5ānM GCN2 and indicated concentrations of ATP in presence of DMSO or compounds. a Ratio of active to total (active + inactive) GCN2 in the reactions with DMSO, 2.5āĪ¼M GSKā414 or 5āĪ¼M AMG44 fit to Michaelis-Menten nonlinear model. Data are shown as meanāĀ±āSD (DMSO nā=ā2, GSKā414 nā=ā3, AMG44 nā=ā4), biologically independent experiments. b Apparent affinity (Kobs) for GCN2 and ATP in presence of compounds from panel (a) normalised to DMSO. Data are shown as meanāĀ±āSD, biologically independent experiments. ***pā<ā0.0007, as determined by one-way ANOVA with Dunnettās multiple comparison test. c As in panel (a) for reactions with DMSO or 0.75āĪ¼M C16 fit to Michaelis-Menten nonlinear model. Data are shown as meanāĀ±āSD (DMSO nā=ā3 and C16 nā=ā4, except 12āĪ¼M ATP nā=ā2 and nā=ā3 respectively), biologically independent experiments. d As in panel (b) for C16 normalised to DMSO. Data are shown as meanāĀ±āSD, biologically independent experiments. *pā<ā0.0231, as determined by two-sided, unpaired t-test. e As in panel (a) for reactions with DMSO, 2āĪ¼M Dovitinib or 1āĪ¼M Neratinib fit to Michaelis-Menten nonlinear model. Data are shown as meanāĀ±āSD (DMSO nā=ā2, Dovitinib nā=ā3, Neratinib nā=ā2), biologically independent experiments. f As in panel (b) for Dovitinib and Neratinib normalised to DMSO. Data are shown as meanāĀ±āSD, biologically independent experiments. **pā<ā0.0045, as determined by one-way ANOVA with Dunnettās multiple comparison test. Source data are provided as a Source data file.
