Selective Inhibition of Mutant Isocitrate Dehydrogenase 1 (IDH1) via Disruption of a Metal Binding Network by an Allosteric Small Molecule

Deng, Gejing; Shen, Junqing; Yin, Ming; McManus, Jessica; Mathieu, Magali; Gee, Patricia; He, Timothy; Shi, Chaomei; Bedel, Olivier; McLean, Larry R.; Le-Strat, Frank; Zhang, Ying; Marquette, Jean‐Pierre; Gao, Qiang; Zhang, Bailin; Rak, Alexey; Hoffmann, Dietmar; Rooney, E.K.; Vassort, Aurélie; Englaro, Walter; Li, Yang; Patel, Vinod F.; Adrián, Francisco; Größ, Stefan; Wiederschain, Dmitri; Cheng, Hong; Licht, Stuart S

doi:10.1074/jbc.m114.608497

Cited by 120 publications

(148 citation statements)

References 36 publications

(53 reference statements)

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“…Inhibitors of IDH1 MT and IDH2 MT were recently developed (23)(24)(25)(26)(27). Clinical trials of the IDH1 R132H inhibitor AGI-5198 (ClinicalTrials.gov NCT02073994) are in progress in solid tumors.…”

Section: Idh1mentioning

confidence: 99%

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

et al. 2015

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Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer to IDH1 R132H , a structural alteration that leads to catalysis of a-ketoglutarate to the oncometabolite D-2-hydroxyglutarate. In this study, we present evidence that small-molecule inhibitors of IDH1 R132H that are being developed for cancer therapy may pose risks with coadministration of radiotherapy. Cancer cells heterozygous for the IDH1 R132H mutation exhibited less IDH-mediated production of NADPH, such that after exposure to ionizing radiation (IR), there were higher levels of reactive oxygen species, DNA double-strand breaks, and cell death compared with IDH1 wild-type cells. These effects were reversed by the IDH1 R132H inhibitor AGI-5198. Exposure of IDH1 wild-type cells to D-2-hydroxyglutarate was sufficient to reduce IDH-mediated NADPH production and increase IR sensitivity. Mechanistic investigations revealed that the radiosensitivity of heterozygous cells was independent of the well-described DNA hypermethylation phenotype in IDH1-mutated cancers. Thus, our results argue that altered oxidative stress responses are a plausible mechanism to understand the radiosensitivity of IDH1-mutated cancer cells. Further, they offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and they imply that administration of IDH1 R132H inhibitors in these patients may limit irradiation efficacy in this setting.

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Section: Idh1mentioning

confidence: 99%

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

et al. 2015

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“…According to these findings, it was suggested that differences in Mg 2+ binding between WT and mutant enzymes may contribute to the selectivity of inhibitors. 100 In the other study, the crystallographic analysis of the structure of another inhibitor (GSK321) bound to mutant IDH1 showed that the inhibitor binds to an allosteric site and freezes the enzyme into an open, catalytically inactive conformation. 100 At variance with the other inhibitor, two molecules of the inhibitor GSK 321 bind per enzyme dimer, and this binding was shown to be competitive with α-KG.…”

Section: Idh Inhibitorsmentioning

confidence: 98%

“…100 In the other study, the crystallographic analysis of the structure of another inhibitor (GSK321) bound to mutant IDH1 showed that the inhibitor binds to an allosteric site and freezes the enzyme into an open, catalytically inactive conformation. 100 At variance with the other inhibitor, two molecules of the inhibitor GSK 321 bind per enzyme dimer, and this binding was shown to be competitive with α-KG. 101 The biologic effect of this inhibitor on primary IDH1-mutant AML blasts was also tested, and showed an initial increase in viable cells, followed by a late reduction in cell viability coupled with an increase in apoptosis, as well as progressive induction of granulocytic differentiation of leukemic cells, as shown by cell morphology and membrane antigen expression.…”

Section: Idh Inhibitorsmentioning

confidence: 98%

“…Two recent studies have more precisely defined the fine molecular mechanisms through which IDH inhibitors determine the blockade of IDHmutant enzyme activity. 100,101 Deng and colleagues reported that a new selective IDH1 inhibitor acts through interaction with a Mg 2+ binding residue that is located at the dimer interface. According to these findings, it was suggested that differences in Mg 2+ binding between WT and mutant enzymes may contribute to the selectivity of inhibitors.…”

Section: Idh Inhibitorsmentioning

confidence: 99%

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Isocitrate Dehydrogenase Mutations in Human Cancers: Physiopathologic Mechanisms and Therapeutic Targeting

2016

JERP

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Isocitrate dehydrogenase (IDH) is a metabolic enzyme responsible for the enzymatic conversion of isocitrate to α-ketoglutarate (α-KG). Mutations in the IDH gene result in a novel gain-offunction, with development of neomorphic enzymatic activity determining the pathological reduction of α-KG to (R)-2-hydroxyglutarate. The accumulation of this pathological metabolite (onco-metabolite) in cancer cells is, to a large extent, responsible for the development of several cancers, including acute myeloid leukemia (AML), low-grade gliomas (LGGs) or chondrocytic tumors. Furthermore, various experimental studies have shown that IDH mutations represent an early, driver event, conserved during tumor progression in neoplasias such AML and LGG. Given all these observations, potent and selective IDH inhibitors have been developed and are currently under investigation in phase I/II clinical studies. In particular, AG-221, a first-in-class inhibitor of mutant IDH2, was tested in hematological patients with refractory/ relapsing AML or myelodysplasia and showed an overall response rate of 59/159 (37%), as well as a good safety profile. Similarly, AG-120, an inhibitor of mutant IDH1, was tested in 66 relapsing/ refractory AML patients and showed an overall response rate of 36%, with a complete response rate of 16%. A new IDH inhibitor, AG-811 displayed the capacity to inhibit both mutants IDH1/2 and to penetrate the blood: brain barrier, a property that would be suitable for treatment of glioma patients. On the other hand, additional observations have suggested that IDH-mutant AMLs are sensitive to treatment with BCL-2 inhibitors and to the differentiative induction with all-trans retinoic acid. In conclusion, the collective studies carried out in recent years on the characterization of IDH-mutant tumors highlight an admirable paradigm of the virtuosic transfer from basic research (with improvements in our understanding of the physio-pathological role played by IDH mutations in the development of some tumors) to clinical studies (with the development of selective, potent and clinically-active IDH inhibitors).

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“…Separate discovery efforts around mutant IDH1 led by Sanofi (Cambridge, MA) (Deng et al, 2015) and GlaxoSmithKline (Collegeville, PA) (Okoye-Okafor et al, 2015) used a similar biochemical screen, although they prepared wild-type-IDH1/ mutant-IDH1 heterodimer protein (physiologic state) using the two most common IDH1 mutations (R132C and R132H) for their screening campaigns. In each case, they pursued distinct chemical scaffolds, and the primary in-cell confirmation of activity was demonstrated through inhibition of 2-HG production.…”

Section: A Case Study 1: Mutant Isocitrate Dehydrogenases 1 Andmentioning

confidence: 99%

Small-Molecule Screens: A Gateway to Cancer Therapeutic Agents with Case Studies of Food and Drug Administration–Approved Drugs

et al. 2017

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Selective Inhibition of Mutant Isocitrate Dehydrogenase 1 (IDH1) via Disruption of a Metal Binding Network by an Allosteric Small Molecule

Cited by 120 publications

References 36 publications

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

Isocitrate Dehydrogenase Mutations in Human Cancers: Physiopathologic Mechanisms and Therapeutic Targeting

Small-Molecule Screens: A Gateway to Cancer Therapeutic Agents with Case Studies of Food and Drug Administration–Approved Drugs

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