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Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2
1Department of Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Beijing Key Laboratory of Tumor Systems Biology, Peking University Health Science Center, Beijing 100191, China.
Abstract:
Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2.
Insights
Mutant isocitrate dehydrogenases (mIDH) drive cancer by producing 2-HG. AG-881 is a novel pan-IDH inhibitor, showing promise for treating mIDH-mutant cancers like glioma and AML.
Area of Science:
- Biochemistry
- Oncology
- Structural Biology
Background:
- Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) lead to the production of the oncometabolite 2-hydroxyglutarate (2-HG), promoting cancer development through epigenetic alterations.
- Targeting mutant IDH (mIDH) is a promising therapeutic strategy for cancers such as glioma and acute myeloid leukemia (AML).
- Existing allosteric inhibitors are specific to either mIDH1 or mIDH2, despite differences in their allosteric inhibition pockets.
Purpose of the Study:
- To elucidate the binding mechanism of the pan-IDH inhibitor AG-881 to both mutant IDH1 (mIDH1) and mutant IDH2 (mIDH2).
- To understand the structural basis for AG-881's inhibitory activity against mIDH1 and mIDH2.
- To provide insights for the future development of novel pan-IDH inhibitors.
Main Methods:
- Determination of crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes.
- Measurement of IC50 values for AG-881 against IDH1-R132H and IDH2-R140Q homodimers following varying pre-incubation times.
- Comparative analysis of AG-881 binding modes within the allosteric pockets of mIDH1 and mIDH2.
Main Results:
- AG-881 binds to both IDH1-R132H and IDH2-R140Q within the same allosteric pockets.
- Subtle differences in the allosteric pockets of mIDH1 and mIDH2 correlate with distinct inhibitory kinetics observed for AG-881.
- Structural and kinetic data reveal the mechanism of pan-inhibition by AG-881.
Conclusions:
- AG-881 effectively inhibits both mIDH1 and mIDH2 by binding to conserved allosteric sites.
- The observed differences in inhibitory kinetics are attributed to subtle structural variations in the allosteric pockets.
- These findings support the potential of AG-881 as a therapeutic agent and guide the design of next-generation pan-IDH inhibitors.
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