New IDH1 mutant inhibitors for treatment of acute myeloid leukemia
Open accessAbstract
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are driver mutations in acute myeloid leukemia (AML) and other cancers. We report the development of new allosteric inhibitors of mutant IDH1. Crystallographic and biochemical results demonstrated that compounds of this chemical series bind to an allosteric site and lock the enzyme in a catalytically inactive conformation, thereby enabling inhibition of different clinically relevant IDH1 mutants. Treatment of IDH1 mutant primary AML cells uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block and induction of granulocytic differentiation at the level of leukemic blasts and more immature stem-like cells, in vitro and in vivo. Molecularly, treatment with the inhibitors led to a reversal of the DNA cytosine hypermethylation patterns caused by mutant IDH1 in the cells of individuals with AML. Our study provides proof of concept for the molecular and biological activity of novel allosteric inhibitors for targeting different mutant forms of IDH1 in leukemia.
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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 Okoye-Okafor et al., 2015
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References 60 · Cited by 180
- Authors
- Okoye-Okafor, U. C., Bartholdy, B., Cartier, J., Gao, E. N., Pietrak, B., Rendina, A. R., Rominger, C., Quinn, C., Smallwood, A., Wiggall, K. J., Reif, A. J., Schmidt, S. J., Qi, H., Zhao, H., Joberty, G., Faelth-Savitski, M., Bantscheff, M., Drewes, G., Duraiswami, C., Brady, P., Groy, A., Narayanagari, S.-R., Antony-Debre, I., Mitchell, K., Wang, H. R., Kao, Y.-R., Christopeit, M., Carvajal, L., Barreyro, L., Paietta, E., Makishima, H., Will, B., Concha, N., Adams, N. D., Schwartz, B., McCabe, M. T., Maciejewski, J., Verma, A., & Steidl, U.
- Affiliations
- Albert Einstein College of Medicine (US)
- GlaxoSmithKline (United States) (US)
- Universität Hamburg (DE)
- Cleveland Clinic (US)
- Corresponding author
- Steidl, Ulrich
- ORCID
- Okoye-Okafor, Ujunwa C
- Bartholdy, Boris
- Cartier, Jessy
- Pietrak, Beth
- Rendina, Alan R
- Reif, Alexander J
- Zhao, Huizhen
- Faelth-Savitski, Maria
- Bantscheff, Marcus
- Drewes, Gerard
- Narayanagari, Swathi-Rao
- Mitchell, Kelly
- Kao, Yun-Ruei
- Christopeit, Maximilian
- Carvajal, Luis
- Barreyro, Laura
- Paietta, Elisabeth
- Makishima, Hideki
- Will, Britta
- Concha, Nestor
- Schwartz, Benjamin
- McCabe, Michael T
- Verma, Amit
- Steidl, Ulrich
- Venue
- Nature Chemical Biology
- Published
- 2015-10-05
- Volume
- 11
- Issue
- 11
- Pages
- 878-886
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5155016
- OpenAlex
- W1887038943
- Cited by
- 180
- References
- 60
- Citations by year
- 2026: 10 · 2025: 15 · 2024: 11 · 2023: 17 · 2022: 12 · 2021: 20 · 2020: 10 · 2019: 15 · 2018: 24 · 2017: 26 · 2016: 18 · 2015: 2
- FWCI
- 18.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (F31CA162770, NIH F31CA162770, R01CA166429, U24CA114737, U10CA180827, P30CA013330)
- National Institute of General Medical Sciences (T32GM007288)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- IDH1 mutation, acute myeloid leukemia, allosteric inhibitors, isocitrate dehydrogenase, 2-hydroxyglutarate, myeloid differentiation, granulocytic differentiation, stem-like cells, crystallography
- MeSH terms
- Allosteric Regulation, Allosteric Site, Animals, Cell Differentiation, Cytosine, Dihydropyridines, Dose-Response Relationship, Drug, Enzyme Inhibitors, Granulocytes, Humans, Isocitrate Dehydrogenase, Kinetics, Male, Models, Molecular, Mutation, Protein Binding, Pyrazoles, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, Crystallography, X-Ray, CpG Islands, DNA Methylation, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice, Primary Cell Culture
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