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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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“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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IDH1/2 mutations in acute myeloid leukemia
Byun, J. M., Yoo, S.-J., Kim, H. J., Ahn, J., Koh, Y., Jang, J. H., & Yoon, S. (2022) · Blood Research · doi:10.5045/br.2021.2021152 · Cited by 33
“Enasidenib (IDH2 inhibitor): Enasidenib (Idhifa) is an oral specific allosteric inhibitor of IDH2 that shows more robust inhibitory effects on IDH2 R172 than on IDH1 R140 mutations, although it has inhibitory effects on both mutations [37].”
BackgroundSuccinate mediates inflammation-induced adrenocortical dysfunction
Mateska, I., Witt, A., Hagag, E., Sinha, A. N., Yılmaz, C., Thanou, E., Sun, N., Kolliniati, O., Patschin, M., Abdelmegeed, H., et al. (2023) · eLife · doi:10.7554/elife.83064 · Cited by 26
Macrocyclization strategy for improving candidate profiles in medicinal chemistry
Darlami, O., Pun, R., Ahn, S., Kim, S., & Shin, D. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116501 · Cited by 28
Enasidenib drives human erythroid differentiation independently of isocitrate dehydrogenase 2
Dutta, R., Zhang, T. Y., Köhnke, T., Thomas, D., Linde, M. H., Gars, E. J., Stafford, M., Kaur, S., Nakauchi, Y., Yin, R. R., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci133344 · Cited by 27
“Because enasidenib has been demonstrated to show moderate inhibitory activity against WT IDH2 at high doses (3), we sought to determine whether the action of enasidenib on erythroid precursors was due to decreased activity of WT IDH2.”
BackgroundMethylation alterations and advance of treatment in lymphoma
Liu, M.-K., Sun, X.-J., Gao, X.-D., Qian, Y., Wang, L., & Zhao, W.-L. (2021) · Frontiers in Bioscience-Landmark · doi:10.52586/4970 · Cited by 30
“In contrast, IDH2 R 140 and IDH1 R 132 mutations that produce less 2-HG are observed in AML but not in AITL [ 56].”
BackgroundKheder, N. A., Ather, H., Emam, D. R., Mahmoud, N. S., Fahim, A. M., & Farag, A. M. (2023) · Polycyclic aromatic compounds · doi:10.1080/10406638.2023.2243639 · Cited by 26
“The results of the docking investigation of synthesized compounds with Crystal Structure of Human Mitochondrial Isocitrate Dehydrogenase R140Q Mutant Homodimer bound to NADPH and alpha-Ketoglutaric acid (PDBID: 5I95) 63 were displayed in Figure 5 and Table 2.”
Chen, J., Yang, J., Sun, X., Wang, Z., Cheng, X., Lu, W., Cai, X., Hu, C., Shen, X., & Cao, P. (2017) · Scientific Reports · doi:10.1038/s41598-017-16427-w · Cited by 29
Decoding mitochondria's role in immunity and cancer therapy
Zhang, Y., YAN, H. H., Wei, Y., & Wei, X. (2024) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2024.189107 · Cited by 30
Molecular Targeting of the Isocitrate Dehydrogenase Pathway and the Implications for Cancer Therapy
Ivanov, S., Nano, O., Hana, C. K., Bonano-Rios, A. M., & Hussein, A. M. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25137337 · Cited by 27
“The most common side effects included indirect hyperbilirubinemia and thrombocytopenia, as well as IDH differentiation syndrome [15].”
BackgroundIsocitrate Dehydrogenase Mutations in Myelodysplastic Syndromes and in Acute Myeloid Leukemias
Testa, U., Castelli, G., & Pelosi, E. (2020) · Cancers · doi:10.3390/cancers12092427 · Cited by 26
“The combined treatment with these two drugs resulted in a marked potentiation of the antileukemic effect, with a pronounced decrease of leukemic blasts and with their differentiation and, particularly, with a decrease of mutant allele burden and progressive recovery of normal hematopoiesis from non-mutant stem-progeni…”
BackgroundLeukemic Stem Cells and Hematological Malignancies
Choi, H.-S., Kim, B. S., Yoon, S., Oh, S., & Lee, D. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25126639 · Cited by 26
“Ivosidenib and enasidenib, mutant IDH1 and IDH2 inhibitors, promote leukemic cell differentiation [158,159].”
BackgroundCathelin, S., Sharon, D. M., Subedi, A., Cojocari, D., Phillips, D. C., Leverson, J. D., MacBeth, K. J., Nicolay, B., Narayanaswamy, R., Ronseaux, S., et al. (2021) · Leukemia · doi:10.1038/s41375-021-01468-y · Cited by 24
“Enasidenib is a first-in-class mutant IDH2 inhibitor that induces differentiation of IDH2-mutated leukemic cells by lowering 2-HG levels [4, 5].”
BackgroundAumer, T., Gremmelmaier, C. B., Runtsch, L. S., Pforr, J. C., Yeşiltaç, G. N., Kaiser, S., & Traube, F. R. (2022) · Clinical Epigenetics · doi:10.1186/s13148-022-01329-0 · Cited by 23
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Self-citationCai, S. F., Huang, Y., Lance, J. R., Mao, H. C., Dunbar, A. J., McNulty, S. N., Druley, T. E., Li, Y., Baer, M. R., Stock, W., et al. (2023) · Blood Advances · doi:10.1182/bloodadvances.2023010563 · Cited by 24
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OncomiR or antioncomiR: Role of miRNAs in Acute Myeloid Leukemia
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“Recent years, the mutations of ten-eleven-translocation (TET1-3) and isocitrate dehydrogenases (IDH1/2) are frequently detected in AML [30,31].”
BackgroundMansouri, K., Rastegari‐Pouyani, M., Ghanbari-Movahed, M., Safarzadeh, M., Kiani, S., & Ghanbari‐Movahed, Z. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110694 · Cited by 24
Targeting Cancer Metabolism and Current Anti-Cancer Drugs
Sukjoi, W., Ngamkham, J., Attwood, P. V., & Jitrapakdee, S. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-55035-6_2 · Cited by 23
Lysine acetylation restricts mutant IDH2 activity to optimize transformation in AML cells
Chen, D., Xia, S., Zhang, R., Li, Y., Famulare, C. A., Fan, H., Wu, R., Wang, M., Zhu, A. C., Elf, S., et al. (2021) · Molecular Cell · doi:10.1016/j.molcel.2021.06.027 · Cited by 25
Connections between metabolism and epigenetic modifications in cancer
Wang, G., & Han, J. J. (2021) · Medical Review · doi:10.1515/mr-2021-0015 · Cited by 27
Yao, K., Liu, H., Yu, S., Zhu, H., & Pan, J. (2022) · Cancer Letters · doi:10.1016/j.canlet.2022.215603 · Cited by 25
Targeting IDH1 and IDH2 Mutations in Acute Myeloid Leukemia: Emerging Options and Pending Questions
Wouters, B. J. (2021) · HemaSphere · doi:10.1097/hs9.0000000000000583 · Cited by 22
Chemical Proteomics Reveals Human Off‐Targets of Fluoroquinolone Induced Mitochondrial Toxicity
Reinhardt, T., Harraoui, Y. E., Rothemann, R. A., Jauch, A. T., Müller-Deubert, S. M., Köllen, M. F., Risch, T., Jacobs, L. H. C., Müller, R., Traube, F. R., et al. (2025) · Angewandte Chemie International Edition · doi:10.1002/anie.202421424 · Cited by 24
Engineering Multidimensional Evolutionary Forces to Combat Cancer
McCoach, C. E., & Bivona, T. G. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-1196 · Cited by 23
“Another example, also from the TCA cycle, is the presence of mutations in isocitrate dehydrogenase (IDH) isoforms 1 and 2 which result in accumulation of high levels of the oncometabolite 2-hydroxylglutarate (161, 162).”
BackgroundGao, M., Zhu, H., Li, F., Li, Y., Bao, X., Fu, H., Quan, H., Wang, L., & Lou, L. (2019) · Cancer Science · doi:10.1111/cas.14152 · Cited by 21
Roussel, X., Daguindau, É., Berceanu, A., Desbrosses, Y., Warda, W., Rocha, M. N. D., Trad, R., Deconinck, É., Deschamps, M., & Ferrand, C. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.599933 · Cited by 24
“org 7 Targeted Therapies IDH1/2-Targeting in Relapse/Refractory AML or Newly Diagnosed Older Non Eligible AML Blockade of IDH1/2-mutated enzyme by inhibitors induces differentiation of malignant blasts (16).”
BackgroundThe landscape of metabolic pathway dependencies in cancer cell lines
Joly, J. H., Chew, B. T. L., & Graham, N. A. (2021) · PLoS Computational Biology · doi:10.1371/journal.pcbi.1008942 · Cited by 25
“For example, leukemias and gliomas with mutations in isocitrate 62 dehydrogenase (IDH) are sensitive to inhibitors specific to mutant IDH [8,9].”
BackgroundDisabling Uncompetitive Inhibition of Oncogenic IDH Mutations Drives Acquired Resistance
Lyu, J., Liu, Y., Gong, L., Chen, M., Madanat, Y. F., Zhang, Y., Cai, F., Gu, Z., Cao, H., Kaphle, P., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1661 · Cited by 23
“Both AG-120 and AG-221 show slow–tight binding inhibition inhibition to IDH1 and IDH2 , respectively (12, 33).”
Influential
Metadata
- 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 › Oncology › 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
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