AG-120 (Ivosidenib) is an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1)[1-2]. AG-120 reduces the levels of the oncogenic metabolite 2-hydroxyglutarate (2-HG) by inhibiting the mutant IDH1 enzyme. AG-120 is used in research related to IDH1-mutant acute myeloid leukemia and cholangiocarcinoma[3-4].
In vitro, AG-120 (0-100nM) was used to treat IDH1-mutant RBE cells, alone or in combination with an HNF4α-overexpressing adenovirus (AdHNF4α) for 3-30 days. AG-120 inhibited cell viability, and the combination treatment significantly enhanced the inhibitory effect on tumor growth[5]. AG-120 (1µM) was combined with gemcitabine (GEM; 10nM) to treat GEM-resistant HuCCT1 and other iCCA cells expressing wild-type IDH1 under low magnesium conditions for 10 days. This combination significantly inhibited cell proliferation, increased intracellular oxidative stress, and decreased the GSH/GSSG ratio[6].
In vivo, AG-120 (75mg/kg; p.o.; twice daily) was administered in combination with 5-FU (30mg/kg; i.p.; twice weekly) for 37 days to nude mice bearing PDX (TM01212) or Mia-Paca2 xenograft tumors. AG-120 significantly inhibited tumor growth and enhanced the antitumor efficacy of the chemotherapeutic agent[7]. AG-120 (150mg/kg; p.o.; once daily) was administered for 28 days to nude mice bearing ICC-9810 cell-derived or patient-derived xenograft tumors. AG-120 significantly suppressed tumor growth and reduced the protein levels of IDH1, NRF2, and HO-1 in the tumor tissues[8].
References:
[1] Popovici-Muller J, Lemieux RM, Artin E, et al. Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers. ACS Med Chem Lett. 2018 Jan 19;9(4):300-305.
[2] Montesinos P, Recher C, Vives S, et al. Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia. N Engl J Med. 2022 Apr 21;386(16):1519-1531.
[3] Abou-Alfa GK, Macarulla T, Javle MM, et al. Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2020 Jun;21(6):796-807.
[4] Mellinghoff IK, Ellingson BM, Touat M, et al. Ivosidenib in Isocitrate Dehydrogenase 1-Mutated Advanced Glioma. J Clin Oncol. 2020 Oct 10;38(29):3398-3406.
[5] Xu BN, Ding CH, Liu YL, et al. HNF4α inhibits the malignancy of intrahepatic cholangiocarcinoma by suppressing the Wnt signaling pathway. Transl Oncol. 2025 Mar;53:102290.
[6] Li X, Song Z, Lin S, et al. The allosteric IDH1 inhibitor ivosidenib overcomes chemoresistance in intrahepatic cholangiocarcinoma models expressing wild-type IDH1. J Clin Invest. 2026 Mar 17:e199730.
[7] Zarei M, Hajihassani O, Hue JJ, et al. IDH1 Inhibition Potentiates Chemotherapy Efficacy in Pancreatic Cancer. Cancer Res. 2024 Sep 16;84(18):3072-3085.
[8] Hao Z, Yang H, Zhu W, et al. ALYREF Promotes Progression of Intrahepatic Cholangiocarcinoma through Increasing the Level of Isocitrate Dehydrogenase 1 in an m5C-Dependent Manner. Mol Cell Biol. 2025;45(5):198-211.