An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells
Open accessAbstract
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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AGI-5198 targets mutant IDH1, reduces intratumoral D-2HG levels, induces expression of genes involved in glial cell differentiation, and suppresses growth of IDH1-mutant human glioma cells in a xenograft model.
“One of the first compounds reported was AGI-5198, which targets mutant IDH1. AGI-5198 reduces intratumoral D-2HG levels, induces expression of genes involved in glial cell differentiation, and suppresses growth of IDH1-mutant human glioma cells in a xenograft model (Rohle et al., 2013).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Rohle 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 Rohle et al., 2013
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References 29 · Cited by 1,153
Research works printed but not linked: 1
- [7]Dang L Nature 2010 465 966 20559394 PMC3766976
- Authors
- Rohle, D., Popovici-Muller, J., Palaskas, N., Turcan, S., Grommes, C., Campos, C., Tsoi, J., Clark, O., Oldrini, B., Komisopoulou, E., Kunii, K., Pedraza, A., Schalm, S., Silverman, L., Miller, A., Wang, F., Yang, H., Chen, Y., Kernytsky, A., Rosenblum, M. K., Liu, W., Biller, S. A., Su, S. M., Brennan, C. W., Chan, T. A., Graeber, T. G., Yen, K. E., & Mellinghoff, I. K.
- Affiliations
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
- Agios Pharmaceuticals, Cambridge, MA 02139, USA.
- Memorial Sloan Kettering Cancer Center (US)
- University of California, Los Angeles (US)
- Agios Pharmaceuticals (United States) (US)
- Corresponding author
- Palaskas, Nicolaos
- Graeber, Thomas G.
- Yen, Katharine E.
- Mellinghoff, Ingo K.
- ORCID
- Venue
- Science
- Published
- 2013-05-03
- Volume
- 340
- Issue
- 6132
- Pages
- 626-630
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3985613
- OpenAlex
- W2047867594
- Cited by
- 1,153
- References
- 29
- Citations by year
- 2026: 40 · 2025: 43 · 2024: 58 · 2023: 48 · 2022: 63 · 2021: 87 · 2020: 97 · 2019: 79 · 2018: 113 · 2017: 110 · 2016: 107 · 2015: 125 · 2014: 122 · 2013: 60 · 2012: 1
- FWCI
- 68.51
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (T32CA160001, U54CA143798, P30CA008748)
- National Institute of Neurological Disorders and Stroke (R01NS080944)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- IDH1 mutation, AGI-5198, 2-hydroxyglutarate, glioma, epigenetic regulation, cancer metabolism, IDH1 inhibitor
- MeSH terms
- Animals, Cell Differentiation, Cell Transformation, Neoplastic, Enzyme Inhibitors, Glioma, Glutarates, Histones, Imidazoles, Isocitrate Dehydrogenase, Methylation, Gene Expression Regulation, Neoplastic, Mice, SCID, Gene Expression Profiling, Xenograft Model Antitumor Assays, RNA Interference, Benzeneacetamides, Mutant Proteins, Mice, Protein Multimerization
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