Fig. 2: Discovery of the indole-based IRE1α RNase inhibitor IA01. | Nature Communications

Fig. 2: Discovery of the indole-based IRE1α RNase inhibitor IA01.

From: Harnessing indole scaffolds to identify small-molecule IRE1α inhibitors modulating XBP1 mRNA splicing

Fig. 2: Discovery of the indole-based IRE1α RNase inhibitor IA01.

a The identification of IA01 as an IRE1α inhibitor hit using a FRET assay. b IA01 inhibited IRE1α and phosphorylated IRE1α RNase activity in the FRET-based assay, with IC50 of 0.30 ± 0.10 μM and 0.32 ± 0.17 μM, respectively. Data are presented as mean ± SEM. n = 3 for IRE1 measurement, n = 4 for p-IRE1α measurement. c IA01 concentration-dependently inhibited phosphorylated IRE1α RNase activity in a gel-based cleavage assay. The expected number of bases was labeled. Representative result of n  =  3. d IA01 stabilized IRE1α concentration-dependently in the DSF assay. n = 2. e IA107 stabilized phosphorylated IREα concentration-dependently in the DSF assay. Left panels, ∆Tm; right panels, melting curve. n = 2. f IA01 bound to IRE1α with a KD of 12.0 ± 9.81 μM (by titrating 200 μM IA01 into 10 μM IRE1α) measured by ITC assay. IRE1α dephosphorylated IRE1α, p-IRE1α phosphorylated IRE1α.

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