Fig. 2: The S280F substitution reduces ivosidenib inhibition and binding. | Nature Communications

Fig. 2: The S280F substitution reduces ivosidenib inhibition and binding.

From: Resistance to the isocitrate dehydrogenase 1 mutant inhibitor ivosidenib can be overcome by alternative dimer-interface binding inhibitors

Fig. 2

a Inhibition (%) of IDH1 variants (400 nM) by ivosidenib (10 µM) as determined by the NADPH absorbance assay. Errors: standard errors of the mean (n = 3 independent replicates measured on the same 96-well plate). Source data are provided as a Source Data file. b KDs determined by non-denaturing MS (20 µM enzyme, technical errors: n = 3 for the z = 19, 20, 21 charge states) and using the CPMG Project pulse NMR sequence (10 µM enzyme, n = 2). Non-denaturing MS: ammonium citrate buffer (200 mM, pH 7.5); CPMG NMR: 50 mM Tris-d11, 100 mM NaCl, 10 mM MgCl2, and 10 % D2O, pH 7.5. c Non-denaturing MS analysis measuring binding of ivosidenib to IDH1 variants. At 20 µM IDH1 variants are predominantly dimeric with 2 NADP(H) molecules bound - dashed line. Green background corresponds to binding of one ivosidenib molecule. Final concentrations of ivosidenib: 5 µM (4:1), 20 µM (1:1), and 160 µM (1:8). Cone-voltage: 100 V.

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