AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations
Published version of a preprint
Abstract
Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate–dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation. In vitro studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human IDH2 mutation–positive acute myeloid leukemia (AML) cells ex vivo and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2R140Q-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with IDH2 mutation–positive advanced hematologic malignancies. Significance: Mutations in IDH1/2 are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. Cancer Discov; 7(5); 478–93. ©2017 AACR. See related commentary by Thomas and Majeti, p. 459. See related article by Shih et al., p. 494. This article is highlighted in the In This Issue feature, p. 443
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AG-221 (enasidenib) inhibits mutant IDH2 and confers survival benefit in a mouse model of IDH2-mutant AML; early results in IDH2-mutant AML patients suggest it can provide clinical benefit.
“A specific inhibitor of mutant IDH2, AG-221 (enasidenib) confers survival benefit in a mouse model of IDH2-mutant AML (Quivoron et al., 2014; Yen et al., 2017) and became the first compound targeting mutant IDH to enter clinical trials in 2014. Early results in IDH2-mutant AML patients have suggested enasidenib can provide clinical benefit (DiNardo et al., 2015; Stein et al., 2014), and this drug”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Yen et al., 2017
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“In preclinical and clinical studies, enasidenib was shown to decrease intracellular 2-HG to normal levels and induce differentiation of mutant-IDH2 immature myeloid precursor and progenitor cells in responding patients [15–17].”
Metabolism, Activity, and Targeting of D- and L-2-Hydroxyglutarates
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“AG-221 inhibited D-2-HG production and induced the differentiation of IDH2mutated primary leukemia cells; it suppressed D-2-HG production and extended survival in tumor xenograft models [113].”
BackgroundWild-type and mutated IDH1/2 enzymes and therapy responses
Molenaar, R. J., Maciejewski, J. P., Wilmink, J. W., & Noorden, C. J. F. V. (2018) · Oncogene · doi:10.1038/s41388-017-0077-z · Cited by 243 · see citing works
“Olaparib, rucaparib, and niraparib are PARP inhibitors [95], and venetoclax is a BCL-2 inhibitor [97] that are all FDAapproved for the treatment of other types of cancer, which may ease future clinical trials with these drugs for the treatment of IDH1/2-mutated cancers.”
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“Enasidenib treatment also significantly prolonged survival in these models (51).”
BackgroundInfluential2-Oxoglutarate-dependent dioxygenases in cancer
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“Ivosidenib and enasidenib bind to allosteric sites, thus stabilizing the open, inactive conformation of the enzymes.(14) The crystal structure model of IDH1-R132H in open conformation (when ivosidenib or an analog is bound) is shown in Figure 5B, indicating the active site with the cofactor NADPH and the location of t…”
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Self-citationOxygen availability and metabolic reprogramming in cancer
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“Although intensive efforts have been made to investigate the cellular functions of IDH-mutant derived D-2HG, and a selective, potent inhibitor of mutant IDH2, AG-221, was shown to be effective in IDH2 mutation-positive acute myeloid leukemia (55, 56), its mirrorimage enantiomer L-2HG is less understood.”
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“The median time from sampling to scFPM report was 5 (1189 33) days, with longer times accounting for re-staining due to updated immunophenotyping 190 data, and to treatment 21 (4-77) days.”
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Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib
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“Mutant IDH2 proteins neomorphically catalyze the oncometabolite, (R)-2-hydroxyglutarate ([R]-2HG).6 High (R)-2HG concentrations promote hypermethylation, altered gene expression, and blocked differentiation of hematopoietic cells.7 Enasidenib suppresses 2HG and induces differentiation of mIDH2 leukemic cells, producin…”
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“The first IDH2 inhibitor AG-221 is developed to inhibit mutant IDH2, reduce 2HG levels, and restore TET2 activity, thereby reversing 5mC accumulation in mouse mIDH AML models [84].”
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“Ivosidenib (AG-120) and enasidenib (AG-221) are first-in-class inhibitors of mutant IDH1 and IDH2 (mIDH1 and mIDH2) (42, 43), respectively, which were recently approved by the FDA for the treatment of AML with IDH1 or IDH2 mutation.”
BackgroundMitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia
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Metabolism and Epigenetic Interplay in Cancer: Regulation and Putative Therapeutic Targets
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“Additionally, AG-221, a first-inclass inhibitor of mutant IDH2, leads to 2HG reduction in IDH2 mutant leukemia and survival benefit in primary human IDH2 mutant AML xenografts (Yen et al., 2017).”
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Epigenetic Targeting of Glioblastoma
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Isocitrate dehydrogenase inhibitors in acute myeloid leukemia
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“The recommended oral dose is 100 mg once daily for at least 6 months or until disease progression or intolerable adverse reaction [53].”
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Reductive carboxylation epigenetically instructs T cell differentiation
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“[56] reported several s-triazine compounds as effective inhibitors against IDH2R140Q, and the initial hit compound 50 was obtained.”
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Metabolomics, metabolic flux analysis and cancer pharmacology
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Glioblastoma Therapy in the Age of Molecular Medicine
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Oncometabolites: A New Paradigm for Oncology, Metabolism, and the Clinical Laboratory
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“In contrast, preclinical and clinical studies, particularly in leukemia, have provided clear rationale for the use of mutant IDH enzyme inhibitors to the point that they are now approved for use in the setting of IDH mutation(56-58).”
BackgroundImportance of R–CF3···O Tetrel Bonding Interactions in Biological Systems
García-Llinás, X., Bauzá, A., Seth, S. K., & Frontera, A. (2017) · The Journal of Physical Chemistry A · doi:10.1021/acs.jpca.7b06052 · Cited by 89 · see citing works
New Targeted Agents in Acute Myeloid Leukemia: New Hope on the Rise
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Metabolomics in drug research and development: The recent advances in technologies and applications
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The Progress and Development of GLUT1 Inhibitors Targeting Cancer Energy Metabolism
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D-2-Hydroxyglutarate in Glioma Biology
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“AGI-6780 is a non-competitive inhibitor of IDH2 mutation, which was reported to reverse IDH2 R140Q induced histone hypermethylation expression (H3K4me3, H3K9me3, H3K27me3, and H3K36me3) in an AML cell model [145].”
BackgroundTargeting Metabolic Reprogramming in Acute Myeloid Leukemia
Castro, I., Sampaio‐Marques, B., & Ludovico, P. (2019) · Cells · doi:10.3390/cells8090967 · Cited by 79 · see citing works
“hypermethylation, and restored myeloid differentiation [97].”
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Mitochondrial metabolism as a target for acute myeloid leukemia treatment
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“4 Enasidenib IDH2 IDH2 R/R AML [190] Phase I/II [191] FDA-approved”
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“Enasidenib binds to the mutated IDH2 protein leading to decreased levels of 2 HG and subsequent cellular differentiation [102].”
BackgroundMitochondria in cancer metabolism, an organelle whose time has come?
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“Enasidinib has been shown to inhibit the production of 2HG in IDH2 mutated AML in preclinical systems [26,27].”
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Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2
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The role of targeted therapy in the management of patients with AML
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“Enasidenib (AG-221) is a covalent inhibitor of R140Q- and R172Kmutated IDH2 and has emerged as the first IDH mutation–specific inhibitor.(27) Of note, enasidenib induced terminal differentiation of leukemic blasts into neutrophils in vivo during these experiments.”
BackgroundDifferentiation therapy of myeloid leukemia: four decades of development
Madan, V., & Koeffler, H. P. (2020) · Haematologica · doi:10.3324/haematol.2020.262121 · Cited by 70 · see citing works
IDH1/IDH2 Inhibition in Acute Myeloid Leukemia
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IDH1: Linking Metabolism and Epigenetics
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Isocitrate dehydrogenase variants in cancer — Cellular consequences and therapeutic opportunities
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“Ivosidenib treatment resulted in decreased levels of intracellular 2-HG, inhibited cellular proliferation, and restored erythropoietin induced differentiation in primary AML cells having an IDH1mutation [138].”
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The role of targeted therapy in the management of patients with AML
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“Enasidenib (AG-221) is a covalent inhibitor of R140Q- and R172Kmutated IDH2 and has emerged as the first IDH mutation–specific inhibitor.(27) Of note, enasidenib induced terminal differentiation of leukemic blasts into neutrophils in vivo during these experiments.”
BackgroundTime to hit pause on mitochondria-targeting cancer therapies
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Metabolic Dysregulations and Epigenetics: A Bidirectional Interplay that Drives Tumor Progression
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“Moreover, AG-221 is a specific inhibitor of the IDH2 mutant, currently under phase I and II investigations, which is shown to reduce 2HG levels in plasma and bone marrow and induce durable remissions in patients with IDH2 mutant advanced hematologic malignancies [21,154].”
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Cancer metabolism and intervention therapy
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The role of enasidenib in the treatment of mutant IDH2 acute myeloid leukemia
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“More recently another potent small-molecule inhibitor AG-221 (enasidenib) was developed that was shown to confer significant survival benefits in a mouse model of IDH mutant leukemia and also in a xenografts model of primary human AML (185).”
Background
- Authors
- Yen, K., Travins, J., Wang, F., David, M. D., Artin, E., Straley, K., Padyana, A., Gross, S., DeLaBarre, B., Tobin, E., Chen, Y., Nagaraja, R., Choe, S., Jin, L., Konteatis, Z., Cianchetta, G., Saunders, J. O., Salituro, F. G., Quivoron, C., Opolon, P., Bawa, O., Saada, V., Paci, A., Broutin, S., Bernard, O. A., de Botton, S., Marteyn, B. S., Pilichowska, M., Xu, Y., Fang, C., Jiang, F., Wei, W., Jin, S., Silverman, L., Liu, W., Yang, H., Dang, L., Dorsch, M., Penard-Lacronique, V., Biller, S. A., & Su, S.-S. M.
- Affiliations
- Agios Pharmaceuticals (United States) (US)
- Inserm (FR)
- 1Agios Pharmaceuticals, Inc., Cambridge, Massachusetts.
- Université Paris-Saclay (FR)
- 6Service de Pharmacologie, Département de Biologie et Pathologie Médicales, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
- 2INSERM U1170, Villejuif, France.
- Tufts Medical Center (US)
- 11ShangPharma, Shanghai, China.
- Viva Biotech (China) (CN)
- Corresponding author
- Su, Shin-San Michael
- ORCID
- Yen, Katharine
- Wang, Fang
- David, Muriel D.
- Padyana, Anil
- Tobin, Erica
- Chen, Yue
- Choe, Sung
- Jin, Lei
- Konteatis, Zenon
- Salituro, Francesco G.
- Quivoron, Cyril
- Opolon, Paule
- Bawa, Olivia
- Saada, Véronique
- Broutin, Sophie
- Bernard, Olivier A.
- Marteyn, Benoît S.
- Pilichowska, Monika
- Jiang, Fan
- Wei, Wentao
- Liu, Wei
- Yang, Hua
- Dang, Lenny
- Venue
- Cancer Discovery
- Published
- 2017-04-30
- Volume
- 7
- Issue
- 5
- Pages
- 478-493
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2588385654
- Cited by
- 471
- References
- 52
- Citations by year
- 2026: 35 · 2025: 47 · 2024: 51 · 2023: 46 · 2022: 48 · 2021: 78 · 2020: 55 · 2019: 37 · 2018: 51 · 2017: 23
- FWCI
- 34.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (INCa-DGOS-Inserm_6043 and INCa 2012-1-RT-09)
- Association pour la Recherche sur le Cancer (SL220130607089)
- Institut National Du Cancer (INCa-DGOS_5733)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- IDH2 inhibitors, acute myeloid leukemia, IDH2 mutation, 2-hydroxyglutarate, oncometabolites, hematopoietic differentiation, TET methylcytosine dioxygenases, histone demethylase, xenograft mouse model
- MeSH terms
- Aminopyridines, Animals, Antineoplastic Agents, Humans, Isocitrate Dehydrogenase, Mutation, Triazines, Leukemia, Myeloid, Acute, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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