ArticleScientific reports2017
Allosteric inhibitor remotely modulates the conformation of the orthestric pockets in mutant IDH2/R140Q.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.Nature communications · 2024Article
- The Interplay between Dysregulated Metabolism and Epigenetics in Cancer.Biomolecules · 2023Review
- IDH2: A novel biomarker for environmental exposure in blood circulatory system disorders.Oncology letters · 2022Review
- How Do Modulators Affect the Orthosteric and Allosteric Binding Pockets?ACS chemical neuroscience · 2022Article
- Put in a "CaCells · 2022Review
- Epigenetic Small-Molecule Modulators Targeting Metabolic Pathways in Cancer.Sub-cellular biochemistry · 2022Article
- Biological Roles and Therapeutic Applications of IDH2 Mutations in Human Cancer.Frontiers in oncology · 2021Review
- Targeting Cancer Metabolism and Current Anti-Cancer Drugs.Advances in experimental medicine and biology · 2021Review
- Identification of a selective inhibitor of IDH2/R140Q enzyme that induces cellular differentiation in leukemia cells.Cell communication and signaling : CCS · 2020Article
- Integrated Computational Approaches and Tools forAllosteric Drug Discovery.International journal of molecular sciences · 2020Review
- Cancer-associated mutation and beyond: The emerging biology of isocitrate dehydrogenases in human disease.Science advances · 2019Review
- Mutant Isocitrate Dehydrogenase Inhibitors as Targeted Cancer Therapeutics.Frontiers in oncology · 2019Review
- Review
Corrections and comments
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Authors and funding
10 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Neomorphic mutation R140Q in the metabolic enzyme isocitrate dehydrogenase 2 (IDH2) is found to be a driver mutation in cancers. Recent studies revealed that allosteric inhibitors could selectively inhibit IDH2/R140Q and induce differentiation of TF-1 erythroleukemia and primary human AML cells. However, the allosteric inhibition mechanism is not very clear. Here, we report the results from computational studies that AGI-6780 binds tightly with the divalent cation binding helices at the homodimer interface and prevents the transition of IDH2/R140Q homodimer to a closed conformation that is required for catalysis, resulting in the decrease of the binding free energy of NADPHs. If the allosteric inhibitor is removed, the original open catalytic center of IDH2/R140Q will gradually reorganize to a quasi-closed conformation and the enzymatic activity might recover. Unlike IDH2/R140Q, AGI-6780 locks one monomer of the wild-type IDH2 in an inactive open conformation and the other in a half-closed conformation, which can be used to explain the selectivity of AGI-6780. Our results suggest that conformational changes are the primary contributors to the inhibitory potency of the allosteric inhibitor. Our study will also facilitate the understanding of the inhibitory and selective mechanisms of AG-221 (a promising allosteric inhibitor that has been approved by FDA) for mutant IDH2.
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