Figure 2 from Repurposing Vandetanib plus Everolimus for the Treatment of <i>ACVR1</i>-Mutant Diffuse Intrinsic Pontine Glioma

Abstract

<p>Validation of vandetanib as an ACVR1 inhibitor and everolimus as a P-gp inhibitor. <b>A,</b> Kinome selectivity map for vandetanib at 10 μmol/L, with red circles reflecting kinases inhibited by >65%. ACVR1 is labeled. The diameter of the circles is inversely proportional to the percentage of kinase activity remaining in the presence of an inhibitor. Taken from the Harvard Medical LINCS KINOMEscan database (<a href="https://lincs.hms.harvard.edu/" target="_blank">https://lincs.hms.harvard.edu/</a>). <b>B,</b> Bar plots showing the IC<sub>50</sub> for various compounds against wild-type (gray) and mutant ACVR1: Q207E, R206H, and G328V (shades of purple). <b>C,</b> Western blot of <i>ACVR1</i><sup>R206H</sup> HSJD-DIPG-007 cells treated with increasing concentrations of vandetanib in the presence of 0.1 μmol/L, 1.0 μmol/L, or 10 μmol/L everolimus. GAPDH is the loading control. <b>D,</b> Bar plots showing apparent permeability (Papp) of a BCRP substrate across a bidirectional cell monolayer (A–B and B–A) in the presence of various inhibitors. <b>E,</b> Bar plots showing apparent permeability (Papp) of a P-gp substrate across a bidirectional cell monolayer (A–B and B–A) in the presence of various inhibitors. Vandetanib, pink; everolimus, light orange; combination, dark red. Error bars represent SD of the mean. ***, <i>P</i> < 0.0001, ANOVA. n.s., not significant. <b>F,</b> Dot plot of vandetanib concentration (Conc) in the brains of normal mice treated with vehicle control (gray), vandetanib (pink), or the combination (dark red), as assessed by mass spectrometry. The black horizontal line represents the median.</p>

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