Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation

Wang, Fang; Travins, Jeremy; DeLaBarre, Byron; Penard-Lacronique, Virginie; Schalm, Stefanie; Hansen, Erica; Straley, Kimberly; Kernytsky, Andrew; Liu, Wei; Gliser, Camelia; Yang, Hua; Gross, Stefan; Artin, Erin; Saada, Veronique; Mylonas, Elena; Quivoron, Cyril; Popovici-Muller, Janeta; Saunders, Jeffrey O.; Salituro, Francesco G.; Yan, Shunqi; Murray, Stuart; Wei, Wentao; Gao, Yi; Dang, Lenny; Dorsch, Marion; Agresta, Sam; Schenkein, David P.; Biller, Scott A.; Su, Shinsan M.; de Botton, Stephane; Yen, Katharine E.

doi:10.1126/science.1234769

Cited by 804Acute Myeloid Leukemia ResearchCancer, Hypoxia, and MetabolismBiochemical Acid Research Studies

Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation

Wang, Fang, Travins, Jeremy, DeLaBarre, Byron, Penard-Lacronique, Virginie, Schalm, Stefanie, Hansen, Erica, Straley, Kimberly, Kernytsky, Andrew +23 more·2013·Science

DOI 10.1126/science.1234769

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Abstract

IDHology: Among the most exciting drug targets to emerge from cancer genome sequencing projects are two related metabolic enzymes, isocitrate dehydrogenases 1 and 2 (IDH1, IDH2). Mutations in the IDH1 and IDH2 genes are common in certain types of human cancer. Whether inhibition of mutant IDH activity might offer therapeutic benefits is unclear (see the Perspective by Kim and DeBerardinis ). F. Wang et al. (p. 622 , published online 4 April) isolated a small molecule that selectively inhibits mutant IDH2, describe the structural details of its binding to the mutant enzyme, and show that this compound suppresses the growth of patient-derived leukemia cells harboring the IDH2 mutation. Rohle et al. (p. 626 , published online 4 April) show that a small molecule inhibitor of IDH1 selectively slows the growth of patient-derived brain tumor cells with the IDH1 mutation.

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Inhibitors of mutant IDH1 or IDH2 induce differentiation in AML cells harboring mutant IDH.
“Inhibitors of mutant IDH1 or IDH2 have been shown to induce differentiation in AML cells harboring mutant IDH (Okoye-Okafor et al., 2015; Wang et al., 2013).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Wang et al., 2013
Small molecule inhibition of mutant IDH1 in glioma and IDH2 in leukemia promotes differentiation.
“Conversely, small molecule-mediated inhibition of mutant IDH1 in glioma and IDH2 in leukemia markedly promoted differentiation in these contexts (Rohle et al., 2013; Wang et al., 2013).”
From The emerging hallmarks of cancer metabolism (2016) · cites this paper as Wang et al., 2013

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Molecular Investigation of Isocitrate Dehydrogenase Gene (IDH) Mutations in Gliomas: First Report of IDH2 Mutations in Indian Patients
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Authors: Wang, F., Travins, J., DeLaBarre, B., Penard-Lacronique, V., Schalm, S., Hansen, E., Straley, K., Kernytsky, A., Liu, W., Gliser, C., Yang, H., Gross, S., Artin, E., Saada, V., Mylonas, E., Quivoron, C., Popovici-Muller, J., Saunders, J. O., Salituro, F. G., Yan, S., Murray, S., Wei, W., Gao, Y., Dang, L., Dorsch, M., Agresta, S., Schenkein, D. P., Biller, S. A., Su, S. M., de Botton, S., & Yen, K. E.
Affiliations: Agios Pharmaceuticals (United States) (US)
Institut National de la Santé et de la Recherche Médicale, INSERM U985, F-94805 Villejuif, France.
Agios Pharmaceuticals, Cambridge, MA, 02139–4169, USA.
Institut Gustave Roussy, F-94805 Villejuif, France.
Université Paris-Sud (FR)
Schrodinger (United States) (US)
Viva Biotech (China) (CN)
Shanghai ChemPartner Co., 998 Halei Road, Pudong New Area, Shanghai, 201203, China.
Corresponding author: Wang, Fang
Travins, Jeremy
DeLaBarre, Byron
Schalm, Stefanie
Yen, Katharine E.
ORCID: Wang, Fang
Schalm, Stefanie
Liu, Wei
Gliser, Camelia
Yang, Hua
Mylonas, Elena
Quivoron, Cyril
Salituro, Francesco G.
Wei, Wentao
Gao, Yi
Dang, Lenny
Yen, Katharine E.
Venue: Science
Publisher: American Association for the Advancement of Science (AAAS)
Published: 2013-05-03
Volume: 340
Issue: 6132
Pages: 622-626
ISSN: 0036-8075 (ISSN-L)
1095-9203
DOI: 10.1126/science.1234769
OpenAlex: W2094851085
Cited by: 804
References: 34
Citations by year: 2026: 24 · 2025: 23 · 2024: 41 · 2023: 32 · 2022: 44 · 2021: 62 · 2020: 64 · 2019: 56 · 2018: 78 · 2017: 80 · 2016: 73 · 2015: 90 · 2014: 90 · 2013: 44 · 2012: 1
FWCI: 71.26
Type: journal article
Language: en
Open access: closed
Locations: Science (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Biochemical Acid Research Studies
Keywords: isocitrate dehydrogenase inhibitors, 2-hydroxyglutarate, allosteric inhibition, small molecule inhibitors, acute myeloid leukemia, erythroleukemia, crystal structure, dimer interface
MeSH terms: Allosteric Site, Antineoplastic Agents, Cells, Cultured, Enzyme Inhibitors, Leukemia, Erythroblastic, Acute, Erythropoiesis, Glutarates, Hematopoiesis, Humans, Isocitrate Dehydrogenase, Phenylurea Compounds, Sulfonamides, Leukemia, Myeloid, Acute, Gene Expression Regulation, Leukemic, Point Mutation, Protein Structure, Secondary, Crystallography, X-Ray, Catalytic Domain, Cell Line, Tumor, Cell Proliferation, Mutant Proteins, Small Molecule Libraries, Protein Multimerization, Molecular Targeted Therapy

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