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AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic IDH2 Mutations
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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
Citations
Cites
Hallmarks of Cancer: The Next Generation
Hanahan, D., & Weinberg, R. A. (2011) · Cell · doi:10.1016/j.cell.2011.02.013 · Cited by 66,590
[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475
Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 29,915
Phaser crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612
NMRPipe: A multidimensional spectral processing system based on UNIX pipes
Delaglio, F., Grzesiek, S., Vuister, G. W., Zhu, G., Pfeifer, J., & Bax, A. (1995) · Journal of Biomolecular NMR · doi:10.1007/bf00197809 · Cited by 15,961
REFMAC 5 for the refinement of macromolecular crystal structures
Murshudov, G. N., Skubák, P., Lebedev, A. A., Pannu, N. S., Steiner, R. A., Nicholls, R. A., Winn, M., Long, F., & Vagin, A. A. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444911001314 · Cited by 8,415
The emerging hallmarks of cancer metabolism
Pavlova, N. N., & Thompson, C. B. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.006 · Cited by 5,926 · cited 1×
“Metabolic reprogramming is a hallmark of cancer, contributing to the initiation and maintenance of tumors (1, 2).”
BackgroundAn Integrated Genomic Analysis of Human Glioblastoma Multiforme
Parsons, D. W., Jones, S., Zhang, X., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G. L., et al. (2008) · Science · doi:10.1126/science.1164382 · Cited by 5,857
IDH1 and IDH2 Mutations in Gliomas
Yan, H., Parsons, D. W., Jin, G., McLendon, R., Rasheed, B. A., Yuan, W., Kos, I., Batinic-Haberle, I., Jones, S., Riggins, G. J., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0808710 · Cited by 5,847
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate
Dang, L., White, D. W., Gross, S., Bennett, B. D., Bittinger, M. A., Driggers, E. M., Fantin, V. R., Jang, H. G., Jin, S., Keenan, M. C., et al. (2009) · Nature · doi:10.1038/nature08617 · Cited by 4,154
Self-citation
Cited by
Sorted by citations
Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design
Meanwell, N. A. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b01788 · Cited by 2,734
Small molecules in targeted cancer therapy: advances, challenges, and future perspectives
Zhong, L., Li, Y., Xiong, L., Wang, W., Wu, M., Yuan, T., Yang, W. M., Tian, C., Miao, Z., Wang, T., et al. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00572-w · Cited by 1,813
Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia
Stein, E. M., DiNardo, C. D., Pollyea, D. A., Fathi, A. T., Roboz, G. J., Altman, J. K., Stone, R. M., DeAngelo, D. J., Levine, R. L., Flinn, I. W., et al. (2017) · Blood · doi:10.1182/blood-2017-04-779405 · Cited by 1,516
“Age, median (range), y 67 (19-100) 67 (19-100) 70 (19-100)”
Self-citationDurable Remissions with Ivosidenib in IDH1 -Mutated Relapsed or Refractory AML
Dinardo, C. D., Stein, E. M., de Botton, S., Roboz, G. J., Altman, J. K., Mims, A. S., Swords, R. T., Collins, R. H., Mannis, G. N., Pollyea, D. A., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1716984 · Cited by 1,507
“Treatment-related AML 14/125 (11) 16/179 (9) 22/242 (9)”
Self-citationTargeting Metabolism for Cancer Therapy
Luengo, A., Gui, D. Y., & Vander Heiden, M. G. (2017) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.08.028 · Cited by 971
“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.”
BackgroundInfluentialMetabolic reprogramming and epigenetic modifications on the path to cancer
Sun, L., Zhang, H., & Gao, P. (2021) · Protein & Cell · doi:10.1007/s13238-021-00846-7 · Cited by 818
“AG-221, another selective inhibitor of the mutant IDH2 enzyme, suppresses 2HG production and induces the differentiation of both human AML cells and mouse model cells (Yen et al., 2017).”
BackgroundTumor biomarkers for diagnosis, prognosis and targeted therapy
Zhou, Y., Tao, L., Qiu, J., Xu, J., Yang, X., Zhang, Y., Tian, X., Guan, X., Cen, X., & Zhao, Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01823-2 · Cited by 836
The emerging role and targetability of the TCA cycle in cancer metabolism
Anderson, N. M., Mucka, P., Kern, J. G., & Feng, H. (2017) · Protein & Cell · doi:10.1007/s13238-017-0451-1 · Cited by 586
“IDH1/2 mutations occur frequently in low-grade glioma and secondary glioblastoma (∼80%), but can also occur in acute myeloid leukemia (20%), angioimmunoblastic T-cell lymphomas (20%), and rarely in other malignancies such as thyroid, colorectal, and prostate cancer (Table 1) (Kang et al., 2009; Yen et al., 2010; Ghiam…”
BackgroundThe impact of cellular metabolism on chromatin dynamics and epigenetics
Reid, M. A., Dai, Z., & Locasale, J. W. (2017) · Nature Cell Biology · doi:10.1038/ncb3629 · Cited by 515
Differentiation therapy revisited
de Thé, H. (2018) · Nature reviews. Cancer · doi:10.1038/nrc.2017.103 · Cited by 462
Challenges and Opportunities in Cancer Drug Resistance
Ward, R. A., Fawell, S. E., Floc’h, N., Flemington, V., McKerrecher, D., & Smith, P. D. (2020) · Chemical Reviews · doi:10.1021/acs.chemrev.0c00383 · Cited by 461
Energy metabolism in health and diseases
Liu, H., Wang, S., Wang, J., Guo, X., Song, Y., Fu, K., Gao, Z., Liu, D., He, W., & Yang, L. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02141-x · Cited by 484
Coupling Krebs cycle metabolites to signalling in immunity and cancer
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398
The implications of IDH mutations for cancer development and therapy
Pirozzi, C. J., & Yan, H. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00521-0 · Cited by 417
The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML
Vetrie, D. L. P., Helgason, G. V., & Copland, M. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-019-0230-9 · Cited by 365
Epigenetics-targeted drugs: current paradigms and future challenges
Dai, W., Qiao, X., Fang, Y., Guo, R., Bai, P., Liu, S., Li, T., Jiang, Y., Wei, S., Na, Z., et al. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02039-0 · Cited by 405
Biological Role and Therapeutic Potential of IDH Mutations in Cancer
Waitkus, M. S., Diplas, B. H., & Yan, H. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.04.011 · Cited by 342
“It is critical to note that the collective results from pre-clinical and clinical studies of IDHmutant leukemia suggest that mutant IDH1/2 inhibitors are efficacious due to a reduction of D2HG levels, which removes a barrier to myeloid differentiation and thus promotes differentiation of mutant IDH-expressing blast ce…”
BackgroundMethodMetabolic Codependencies in the Tumor Microenvironment
Dey, P., Kimmelman, A. C., & DePinho, R. A. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1211 · Cited by 349
Stein, E. M., Dinardo, C. D., Fathi, A. T., Pollyea, D. A., Stone, R. M., Altman, J. K., Roboz, G. J., Patel, M. R., Collins, R. H., Flinn, I. W., et al. (2018) · Blood · doi:10.1182/blood-2018-08-869008 · Cited by 330
Self-citationTargeting mitochondrial metabolism for precision medicine in cancer
Sainero‐Alcolado, L., Liaño-Pons, J., Ruiz-Pérez, M. V., & Arsenian‐Henriksson, M. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01022-y · Cited by 338
“Notably, AG-221 [34] and AG881 [35] are in clinical trials for treatment of acute myelogenous leukemia carrying IDH2 or IDH1/2 mutations, respectively.”
BackgroundTowards precision medicine for AML
Döhner, H., Wei, A. H., & Löwenberg, B. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00509-w · Cited by 319
Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations
Intlekofer, A. M., Shih, A. H., Wang, B., Nazir, A., Rustenburg, A. S., Albanese, S. K., Patel, M., Famulare, C., Correa, F. M., Takemoto, N., et al. (2018) · Nature · doi:10.1038/s41586-018-0251-7 · Cited by 281
Self-citationMitochondria Targeting as an Effective Strategy for Cancer Therapy
Ghosh, P., Vidal, C., Dey, S., & Li, Z. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21093363 · Cited by 272
Kalev, P., Hyer, M. L., Größ, S., Konteatis, Z. D., Chen, C.-C., Fletcher, M., Lein, M., Aguado-Fraile, E., Frank, V. E., Barnett, A., et al. (2021) · Cancer Cell · doi:10.1016/j.ccell.2020.12.010 · Cited by 267
Self-citationPollyea, D. A., Tallman, M. S., de Botton, S., Kantarjian, H. M., Collins, R. H., Stein, A. S., Frattini, M. G., Xu, Q., Tosolini, A., See, W. L., et al. (2019) · Leukemia · doi:10.1038/s41375-019-0472-2 · Cited by 253
“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
Ye, D., Guan, K.-L., & Xiong, Y. (2018) · Trends in Cancer · doi:10.1016/j.trecan.2017.12.005 · Cited by 242
“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 249
“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.”
Waarts, M. R., Stonestrom, A. J., Park, Y. C., & Levine, R. L. (2022) · Journal of Clinical Investigation · doi:10.1172/jci154943 · Cited by 249
Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics
Golub, D., Iyengar, N. S., Dogra, S., Wong, T., Bready, D., Tang, K., Modrek, A. S., & Placantonakis, D. G. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00417 · Cited by 234
“Enasidenib treatment also significantly prolonged survival in these models (51).”
BackgroundInfluential2-Oxoglutarate-dependent dioxygenases in cancer
Losman, J.-A., Koivunen, P., & Kaelin, W. G. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-00303-3 · Cited by 241
Cancer Metabolism: Current Understanding and Therapies
Counihan, J. L., Grossman, E. A., & Nomura, D. K. (2018) · Chemical Reviews · doi:10.1021/acs.chemrev.7b00775 · Cited by 236
Nacev, B. A., Jones, K. B., Intlekofer, A. M., Yu, J., Allis, C. D., Tap, W. D., Ladanyi, M., & Nielsen, T. O. (2020) · Nature reviews. Cancer · doi:10.1038/s41568-020-0288-4 · Cited by 214
Choe, S. E., Wang, H., Dinardo, C. D., Stein, E. M., de Botton, S., Roboz, G. J., Altman, J. K., Mims, A. S., Watts, J. M., Pollyea, D. A., et al. (2020) · Blood Advances · doi:10.1182/bloodadvances.2020001503 · Cited by 218
“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…”
BackgroundSelf-citationKonteatis, Z. D., Artin, E., Nicolay, B., Straley, K. S., Padyana, A. K., Jin, L., Chen, Y., Narayaraswamy, R., Tong, S., Wang, F., et al. (2020) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.9b00509 · Cited by 217
Self-citationOxygen availability and metabolic reprogramming in cancer
Xie, H. J., & Simon, M. C. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.799973 · Cited by 207
“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.”
BackgroundKornauth, C., Pemovska, T., Vladimer, G. I., Bayer, G., Bergmann, M., Eder, S., Eichner, R., Erl, M., Esterbauer, H., Exner, R., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0538 · Cited by 206
“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.”
Dinardo, C. D., Schuh, A. C., Stein, E. M., Montesinos, P., Wei, A. H., de Botton, S., Zeidan, A. M., Fathi, A. T., Kantarjian, H. M., Bennett, J. M., et al. (2021) · The Lancet Oncology · doi:10.1016/s1470-2045(21)00494-0 · Cited by 199
Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib
Quek, L. S., David, M. D., Kennedy, A., Metzner, M., Amatangelo, M. D., Shih, A. H., Stoilova, B., Quivoron, C., Heiblig, M., Willekens, C., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0115-6 · Cited by 199
Self-citationFathi, A. T., Dinardo, C. D., Kline, I., Kenvin, L., Gupta, I. V., Attar, E. C., Stein, E. M., de Botton, S., & for the AG221-C-001 Study Investigators (2018) · JAMA Oncology · doi:10.1001/jamaoncol.2017.4695 · Cited by 195
“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…”
BackgroundInfluentialAcute myeloid leukemia with IDH1 and IDH2 mutations: 2021 treatment algorithm
Issa, G. C., & Dinardo, C. D. (2021) · Blood Cancer Journal · doi:10.1038/s41408-021-00497-1 · Cited by 209
Is Mitochondrial Dysfunction a Common Root of Noncommunicable Chronic Diseases?
Díaz‐Vegas, A., Sánchez-Aguilera, P., Krycer, J. R., Morales, P. E., Monsalves‐Álvarez, M., Cifuentes, M., Rothermel, B. A., & Lavandero, S. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa005 · Cited by 179
Tommasini-Ghelfi, S., Murnan, K., Kouri, F. M., Mahajan, A., May, J., & Stegh, A. H. (2019) · Science Advances · doi:10.1126/sciadv.aaw4543 · Cited by 166
Precision therapy for acute myeloid leukemia
Yang, X. W., & Wang, J. (2018) · Journal of Hematology & Oncology · doi:10.1186/s13045-017-0543-7 · Cited by 161
“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].”
BackgroundWu, M., Shi, L., Dubrot, J., Merritt, J., Vijay, V., Wei, T.-Y., Kessler, E., Olander, K. E., Adil, R., Pankaj, A., et al. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-1077 · Cited by 158
Jones, C. L., Sheth, A. I., & Jordan, C. T. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.02.013 · Cited by 166
Systemic Immunometabolism: Challenges and Opportunities
Lercher, A., Baazim, H., & Bergthaler, A. (2020) · Immunity · doi:10.1016/j.immuni.2020.08.012 · Cited by 144
Oncogenic Activities of IDH1/2 Mutations: From Epigenetics to Cellular Signaling
Gagné, L. M., Boulay, K., Topisirović, I., Huot, M., & Mallette, F. A. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.06.002 · Cited by 143
Clinical development of metabolic inhibitors for oncology
Lemberg, K. M., Gori, S. S., Tsukamoto, T., Rais, R., & Slusher, B. S. (2022) · Journal of Clinical Investigation · doi:10.1172/jci148550 · Cited by 142
“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
Stuani, L., Sabatier, M., Wang, F., Poupin, N., Bosc, C., Saland, E., Castelli, F. A., Gales, L., Montersino, C., Boët, E., et al. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20200924 · Cited by 143
Self-citationOchocki, J. D., Khare, S., Hess, M., Ackerman, D., Qiu, B., Daisak, J. I., Worth, A. J., Lin, N., Lee, P., Xie, H. J., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.04.009 · Cited by 128
Wang, F., Morita, K., Dinardo, C. D., Furudate, K., Tanaka, T. N., Yan, Y., Patel, K. P., MacBeth, K. J., Wu, B., Liu, G., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22874-x · Cited by 137
Self-citationSi, X., Shao, M., Teng, X., Huang, Y., Ye, M., Wu, L., Wei, J., Liu, L., Gu, T., Song, J., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.12.010 · Cited by 127
Metabolism and Epigenetic Interplay in Cancer: Regulation and Putative Therapeutic Targets
Miranda‐Gonçalves, V., Lameirinhas, A., Henrique, R., & Jerónimo, C. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00427 · Cited by 125
“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).”
Backgroundde Botton, S., Montesinos, P., Schuh, A. C., Papayannidis, C., Vyas, P., Wei, A. H., Ommen, H. B., Семочкин, С. В., Kim, H., Larson, R. A., et al. (2022) · Blood · doi:10.1182/blood.2021014901 · Cited by 124
Cardio-onco-metabolism: metabolic remodelling in cardiovascular disease and cancer
Karlstaedt, A., Moslehi, J. J., & de Boer, R. A. (2022) · Nature Reviews Cardiology · doi:10.1038/s41569-022-00698-6 · Cited by 130
Epigenetic Targeting of Glioblastoma
Romani, M., Pistillo, M. P., & Banelli, B. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00448 · Cited by 119
Fluorine in the Pharmaceutical Industry: FDA‐Approved Fluorine‐Containing Drugs in 2024
Du, Y., Bian, Y., Baecker, D., Dhawan, G., Semghouli, A., Kiss, L., Zhang, W., Sorochinsky, A. E., Soloshonok, V. A., & Han, J. (2025) · Chemistry - A European Journal · doi:10.1002/chem.202500662 · Cited by 124
Schießer, S., Chepliaka, H., Kollback, J., Quennesson, T., Czechtizky, W., & Cox, R. J. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01457 · Cited by 114
Isocitrate dehydrogenase inhibitors in acute myeloid leukemia
Liu, X., & Gong, Y. (2019) · Biomarker Research · doi:10.1186/s40364-019-0173-z · Cited by 111
“The recommended oral dose is 100 mg once daily for at least 6 months or until disease progression or intolerable adverse reaction [53].”
BackgroundStein, E. M., Fathi, A. T., Dinardo, C. D., Pollyea, D. A., Roboz, G. J., Collins, R. H., Sekeres, M. A., Stone, R. M., Attar, E. C., Frattini, M. G., et al. (2020) · The Lancet Haematology · doi:10.1016/s2352-3026(19)30284-4 · Cited by 109
Reductive carboxylation epigenetically instructs T cell differentiation
Jaccard, A., Wyss, T., Maldonado‐Pérez, N., Rath, J. A., Bevilacqua, A., Peng, J.-J., Lepez, A., Gunten, C. V., Franco, F., Kao, K., et al. (2023) · Nature · doi:10.1038/s41586-023-06546-y · Cited by 105
Antitumor Activity of s-Triazine Derivatives: A Systematic Review
Dai, Q., Sun, Q., Ouyang, X., Liu, J., Jin, L., Liu, A., He, B., Fan, T., & Jiang, Y. (2023) · Molecules · doi:10.3390/molecules28114278 · Cited by 100
“[56] reported several s-triazine compounds as effective inhibitors against IDH2R140Q, and the initial hit compound 50 was obtained.”
BackgroundSelf-citationEmerging Applications of Metabolomics in Clinical Pharmacology
Pang, H., Jia, W. P., & Hu, Z. (2019) · Clinical Pharmacology & Therapeutics · doi:10.1002/cpt.1538 · Cited by 95
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Liang, L., Sun, F., Wang, H., & Hu, Z. (2021) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107827 · Cited by 99
Interplay between Cellular Metabolism and the DNA Damage Response in Cancer
Moretton, A., & Loizou, J. I. (2020) · Cancers · doi:10.3390/cancers12082051 · Cited by 97
Ocaña, M. C., Martı́nez-Poveda, B., Quesada, A. R., & Medina, M. Á. (2018) · Medicinal Research Reviews · doi:10.1002/med.21511 · Cited by 92
Glioblastoma Therapy in the Age of Molecular Medicine
Geraldo, L. H., Garcia, C., da Fonseca, A. C. C., Dubois, L. G., Spohr, T. C. L. D. S. E., Matias, D., Magalhães, E. S. D. C., do Amaral, R. F., da Rosa, B. G., Grimaldi, I., et al. (2018) · Trends in cancer · doi:10.1016/j.trecan.2018.11.002 · Cited by 93
Oncometabolites: A New Paradigm for Oncology, Metabolism, and the Clinical Laboratory
Collins, R. R. J., Patel, K., Putnam, W. C., Kapur, P., & Rakheja, D. (2017) · Clinical Chemistry · doi:10.1373/clinchem.2016.267666 · Cited by 94
Shelar, S. B., Shim, E., Brinkley, G. J., Kundu, A., Carobbio, F., Poston, T. L., Tan, J. C., Parekh, V., Benson, D. G., Crossman, D. K., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-18-1727 · Cited by 89
“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
New Targeted Agents in Acute Myeloid Leukemia: New Hope on the Rise
Bohl, S., Bullinger, L., & Rücker, F. G. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20081983 · Cited by 89
Metabolomics in drug research and development: The recent advances in technologies and applications
Pang, H., & Hu, Z. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.05.021 · Cited by 89
The Progress and Development of GLUT1 Inhibitors Targeting Cancer Energy Metabolism
Meng, Y., Xu, X. J., Luan, H., Li, L., Dai, W., Li, Z., & Bian, J. (2019) · Future Medicinal Chemistry · doi:10.4155/fmc-2019-0052 · Cited by 85
Xuan, L., & Liu, Q. (2021) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-01017-7 · Cited by 82
D-2-Hydroxyglutarate in Glioma Biology
Chou, F.-J., Liu, Y., Lang, F., & Yang, C. (2021) · Cells · doi:10.3390/cells10092345 · Cited by 87
“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
“hypermethylation, and restored myeloid differentiation [97].”
Hou, H., & Tien, H. (2020) · Journal of Biomedical Science · doi:10.1186/s12929-020-00674-7 · Cited by 86
Mitochondrial metabolism as a target for acute myeloid leukemia treatment
Panina, S., Pei, J., & Kirienko, N. V. (2021) · Cancer & Metabolism · doi:10.1186/s40170-021-00253-w · Cited by 74
“4 Enasidenib IDH2 IDH2 R/R AML [190] Phase I/II [191] FDA-approved”
Leisch, M., Jansko, B., Zaborsky, N., Greil, R., & Pleyer, L. (2019) · Cancers · doi:10.3390/cancers11020252 · Cited by 76
“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?
Anderson, R. G., Ghiraldeli, L. P., & Pardee, T. S. (2018) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2018.05.005 · Cited by 76
“Enasidinib has been shown to inhibit the production of 2HG in IDH2 mutated AML in preclinical systems [26,27].”
BackgroundNakagawa, M., Nakatani, F., Matsunaga, H., Seki, T., Endo, M., Ogawara, Y., Machida, Y., Katsumoto, T., Yamagata, K., Hattori, A., et al. (2019) · Oncogene · doi:10.1038/s41388-019-0929-9 · Cited by 78
Differentiation therapy for myeloid malignancies: beyond cytotoxicity
Stubbins, R. J., & Karsan, A. (2021) · Blood Cancer Journal · doi:10.1038/s41408-021-00584-3 · Cited by 75
Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2
Ma, R., & Yun, C. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.08.068 · Cited by 73
The role of targeted therapy in the management of patients with AML
Perl, A. E. (2017) · Hematology · doi:10.1182/asheducation-2017.1.54 · Cited by 71
“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 72
IDH1/IDH2 Inhibition in Acute Myeloid Leukemia
Cerchione, C., Romano, A., Daver, N. G., Dinardo, C. D., Jabbour, E. J., Konopleva, M. Y., Ravandi‐Kashani, F., Kadia, T. M., Martelli, M. P., Isidori, A., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.639387 · Cited by 73
IDH1: Linking Metabolism and Epigenetics
Raineri, S., & Mellor, J. (2018) · Frontiers in Genetics · doi:10.3389/fgene.2018.00493 · Cited by 70
Isocitrate dehydrogenase variants in cancer — Cellular consequences and therapeutic opportunities
Liu, S., Cadoux-Hudson, T. A. D., & Schofield, C. J. (2020) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2020.06.012 · Cited by 70
Kirtonia, A., Pandya, G., Sethi, G., Pandey, A. K., Das, B. C., & Garg, M. (2020) · Journal of Molecular Medicine · doi:10.1007/s00109-020-01944-5 · Cited by 68
“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].”
BackgroundDuchmann, M., Micol, J., Duployez, N., Raffoux, E., Thomas, X., Marolleau, J., Braun, T., Adès, L., Chantepie, S., Lemasle, É., et al. (2021) · Blood · doi:10.1182/blood.2020010165 · Cited by 66
The role of targeted therapy in the management of patients with AML
Perl, A. E. (2017) · Blood Advances · doi:10.1182/bloodadvances.2017009829 · Cited by 68
“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
Zhang, X., & Dang, C. V. (2023) · Nature Medicine · doi:10.1038/s41591-022-02129-y · Cited by 65
Mito, J. K., Bishop, J. A., Sadow, P. M., Stelow, E. B., Faquin, W. C., Mills, S. E., Krane, J. F., French, C. A., Fletcher, C. D. �., Hornick, J. L., et al. (2018) · The American Journal of Surgical Pathology · doi:10.1097/pas.0000000000001064 · Cited by 64
Time to repeal and replace response criteria for acute myeloid leukemia?
Bloomfield, C. D., Estey, E. H., Pleyer, L., Schuh, A. C., Stein, E. M., Tallman, M. S., & Wei, A. H. (2018) · Blood Reviews · doi:10.1016/j.blre.2018.03.006 · Cited by 63
Metabolic Dysregulations and Epigenetics: A Bidirectional Interplay that Drives Tumor Progression
Crispo, F., Condelli, V., Lepore, S., Notarangelo, T., Sgambato, A., Esposito, F., Maddalena, F., & Landriscina, M. (2019) · Cells · doi:10.3390/cells8080798 · Cited by 63
“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].”
BackgroundKhan, M. A., Zubair, H., Anand, S., Srivastava, S. K., Singh, S., & Singh, A. P. (2020) · Cancer Letters · doi:10.1016/j.canlet.2020.01.003 · Cited by 61
Cancer metabolism and intervention therapy
Zhao, H., & Li, Y. (2021) · Molecular Biomedicine · doi:10.1186/s43556-020-00012-1 · Cited by 67
Allemailem, K. S., Almatroudi, A., Alsahli, M. A., Aljaghwani, A., El-Kady, A. M., Rahmani, A. H., & Khan, A. A. (2021) · International Journal of Nanomedicine · doi:10.2147/ijn.s303832 · Cited by 61
The role of enasidenib in the treatment of mutant IDH2 acute myeloid leukemia
Dalle, I. A., & Dinardo, C. D. (2018) · Therapeutic Advances in Hematology · doi:10.1177/2040620718777467 · Cited by 60
Sun, Y., Chen, B.-R., & Deshpande, A. J. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00041 · Cited by 64
“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
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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