AGI-6780 is an orally active, potent and selective mutant isocitrate dehydrogenase 2 (IDH2R140Q) inhibitor (IC₅₀=23±1.7nM). AGI-6780 allosterically binds at the IDH2 dimer interface to noncompetitively inhibit the substrate and uncompetitively inhibit the NADPH cofactor, thereby blocking the gain-of-function activity of mutant IDH2 (especially R140Q). AGI-6780 can be used in research related to acute myeloid leukemia (AML) and other IDH2 mutation-associated tumors (e.g., low-grade gliomas)[1-4].
In vitro, AGI-6780 (2-4µM) had been applied to treat K562 cells and imatinib/adriamycin-resistant K562 cells for 48h. AGI-6780 had shown little effect on the basal survival of K562 cells. AGI-6780 had reduced the IC₅₀ of resistant K562 cells to imatinib or adriamycin[5]. AGI-6780 (5µM) had been used to treat multiple myeloma cell lines, mantle cell lymphoma and Burkitt lymphoma cell lines for 96h. AGI-6780 had impaired tricarboxylic acid cycle activity and mitochondrial ATP production in these cells, promoted cell cycle arrest at G0/G1 phase accompanied by cyclin downregulation, PARP-1 cleavage, and caspase-3/7/9 activation, thereby enhancing tumor cell death[6].
In vivo, AGI-6780 (60mg/kg; single injection) had been intraperitoneally administered to C57BL/6J mice, followed 30min later by an intraperitoneal glucose load (1.5g/kg) for an intraperitoneal glucose tolerance test. AGI-6780 had achieved a plasma drug concentration of approximately 15µM maintained between 30 and 90min, had abolished the normal insulin secretory response to glucose stimulation, and had significantly reduced circulating glucagon levels[7]. AGI-6780 (25mg/kg/day and 50mg/kg/day) had been intraperitoneally injected into BALB/c nude mice bearing orthotopic xenografts of MDA-MB-231 triple-negative breast cancer (starting when tumor diameter reached approximately 5-6mm) for 6 consecutive weeks. AGI-6780 had inhibited tumor growth in a dose-dependent manner[8].
References:
[1] Chen Y, Feng X, Yin X, et al. Prognostic and immunological role of RHEBL1 in pan-cancer: a target for survival and immunotherapy. Discov Oncol. 2025 May 14;16(1):766.
[2] Kim J, DeBerardinis RJ. Cancer. Silencing a metabolic oncogene. Science. 2013 May 3;340(6132):558-9.
[3] Chen J, Yang J, Sun X, et al. Allosteric inhibitor remotely modulates the conformation of the orthestric pockets in mutant IDH2/R140Q. Sci Rep. 2017 Nov 28;7(1):16458.
[4] Li J, He Y, Tan Z, et al. Wild-type IDH2 promotes the Warburg effect and tumor growth through HIF1α in lung cancer. Theranostics. 2018 Jul 16;8(15):4050-4061.
[5] Liu W, Sun Y, Ge W, et al. DIA-Based Proteomics Identifies IDH2 as a Targetable Regulator of Acquired Drug Resistance in Chronic Myeloid Leukemia. Mol Cell Proteomics. 2022 Feb;21(2):100187.
[6] Bergaggio E, Riganti C, Garaffo G, et al. IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies. Blood. 2019 Jan 10;133(2):156-167.
[7] Zhang GF, Jensen MV, Gray SM, et al. Reductive TCA cycle metabolism fuels glutamine- and glucose-stimulated insulin secretion. Cell Metab. 2021 Apr 6;33(4):804-817.e5.
[8] Li JJ, Yu T, Zeng P, et al. Wild-type IDH2 is a therapeutic target for triple-negative breast cancer. Nat Commun. 2024 Apr 24;15(1):3445.