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. 2022 May 23;10(5):e004644. doi: 10.1136/jitc-2022-004644

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© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

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Inhibition of IDH1^R132H suppresses 2-HG production and tumor growth in vivo. (A) Inhibition of IDH1^R132H activity by AG-120 and AG-881 in vitro. Levels of 2-HG in the supernatant of dTG-IDH1^R132H cells cultured in different concentrations of AG-881 (green) or AG-120 (purple) were examined by LC-MS/MS to determine the IC50 values for each inhibitor’s activity. (B) Levels of AG-881 (black) and AG-120 (pink) detected in the brain of dTG mice bearing dTG-IDH1^R132H tumors. Beginning 7 days after the tumor inoculation, animals received oral administrations of vehicle or the corresponding inhibitor for 4 days. Samples were collected 1, 4, 12, and 24 hours after final drug administration and analyzed for the concentration of AG-881 and AG-120. (C) Both AG-881 and AG-120 suppressed intratumoral levels of 2-HG. Pharmacodynamics of AG-881 (black) and AG-120 (pink) in vivo were determined by analyzing the levels of 2-HG in samples from (B). (D, E) Tumor growth was significantly delayed by AG-881 treatment. Tumor-bearing mice were randomized to receive daily p.o. administration of AG-881 (n=5) or vehicle (n=4) beginning on day 7 post-tumor inoculation. (D) The tumor size, determined by BLI, and (E) weight of each mouse were measured every 3–4 days after treatment initiation and ended when control mice reached the protocol-specified endpoint due to tumor burden. BLI, bioluminescent imaging; dTG, double transgenic; HG, hydroxyglutarate.