AG-221, an Oral, Selective, First-in-Class, Potent IDH2-R140Q Mutant Inhibitor, Induces Differentiation in a Xenotransplant Model

Quivoron, Cyril; David, Muriel D.; Straley, Kim; Travins, Jeremy; Kim, Hyeryun; Chen, Yue; Zhu, Dongwei; Saada, Véronique; Bawa, Olivia; Opolon, Paule; Polrot, Mélanie; Micol, Jean-Baptiste; Willekens, Christophe; Bernard, Olivier; Yang, Hua; Agresta, Sam; Botton, Stéphane de; Yen, Katharine; Penard-Lacronique, Virginie

doi:10.1182/blood.v124.21.3735.3735

Cited by 19 publications

(8 citation statements)

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“…In principle, small molecules are designed to bind within the active catalytic site of a mutant IDH1/2 and block the conformational change required for the enzyme to convert α-KG to 2-HG [ 67 ]. Consequently, targeted inhibition of mutated IDH1/2 results in decreased intracellular and serum levels of 2-HG [ 68 , 69 ], followed by reversion of global alterations in an epigenome. Current targeted inhibitors of IDH1 (AG120, IDH305), IDH2 (AG221), and pan- IDH1/2 (AG881) selectively inhibit the mutant IDH activity and induce cell differentiation in in vitro and in vivo models.…”

Section: Targeting Of Mutant Idh1/2 Gliomas With Isoform-specific mentioning

confidence: 99%

“…AG-221 reduced serum levels of 2-HG and induced myeloid differentiation of AML leukemic blast cells engrafted to immunodeficient mice. AG-221 is currently being evaluated in several clinical trials for the use in advanced hematologic malignancies positive for a mutated IDH2 [ 69 ]. AG-221 decreased 2-HG level in marrow, plasma, and urine of xenotransplant mice, and promoted significant survival benefits in a dose-dependent manner [ 82 ].…”

Section: Targeting Of Mutant Idh1/2 Gliomas With Isoform-specific mentioning

confidence: 99%

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Consequences of IDH1/2 Mutations in Gliomas and an Assessment of Inhibitors Targeting Mutated IDH Proteins

et al. 2019

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Isocitrate dehydrogenases (IDH) 1 and 2 are key metabolic enzymes that generate reduced nicotinamide adenine dinucleotide phosphate (NADPH) to maintain a pool of reduced glutathione and peroxiredoxin, and produce α-ketoglutarate, a co-factor of numerous enzymes. IDH1/2 is mutated in ~70–80% of lower-grade gliomas and the majority of secondary glioblastomas. The mutant IDH1 (R132H), in addition to losing its normal catalytic activity, gains the function of producing the d-(R)-2-hydroxyglutarate (2-HG). Overproduction of 2-HG in cancer cells interferes with cellular metabolism and inhibits histone and DNA demethylases, which results in histone and DNA hypermethylation and the blockade of cellular differentiation. We summarize recent findings characterizing molecular mechanisms underlying oncogenic alterations associated with mutated IDH1/2, and their impact on tumor microenvironment and antitumor immunity. Isoform-selective IDH inhibitors which suppress 2-HG production and induce antitumor responses in cells with IDH1 and IDH2 mutations were developed and validated in preclinical settings. Inhibitors of mutated IDH1/2 enzymes entered clinical trials and represent a novel drug class for targeted therapy of gliomas. We describe the development of small-molecule compounds and peptide vaccines targeting IDH-mutant gliomas and the results of their testing in preclinical and clinical studies. All those results support the translational potential of strategies targeting gliomas carrying IDH1 mutations.

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Section: Targeting Of Mutant Idh1/2 Gliomas With Isoform-specific mentioning

confidence: 99%

Section: Targeting Of Mutant Idh1/2 Gliomas With Isoform-specific mentioning

confidence: 99%

Consequences of IDH1/2 Mutations in Gliomas and an Assessment of Inhibitors Targeting Mutated IDH Proteins

et al. 2019

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“…In gliomas, the use of hypomethylating agents reduced DNA methylation of promoters involved in glial cell differentiation and reduced cell proliferation in human derived IDH1 mutant glioma xenografts [ 107 , 108 ]. IDH mutant inhibitors, like AGI-5198 and AGI-6780, have been tested preclinically and reduced 2HG levels, reversed histone and DNA hypermethylation, and promoted cell differentiation [ 109 , 110 , 111 , 112 ]. Some of these inhibitors are currently being evaluated in phase I clinical trials [ 113 ].…”

Section: Production Of Oncometabolites and Effects On Normal Metabmentioning

confidence: 99%

Metabolic Alterations in Cancer Cells and the Emerging Role of Oncometabolites as Drivers of Neoplastic Change

2018

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The mitochondrion is an important organelle and provides energy for a plethora of intracellular reactions. Metabolic dysregulation has dire consequences for the cell, and alteration in metabolism has been identified in multiple disease states—cancer being one. Otto Warburg demonstrated that cancer cells, in the presence of oxygen, undergo glycolysis by reprogramming their metabolism—termed “aerobic glycolysis”. Alterations in metabolism enable cancer cells to gain a growth advantage by obtaining precursors for macromolecule biosynthesis, such as nucleic acids and lipids. To date, several molecules, termed “oncometabolites”, have been identified to be elevated in cancer cells and arise from mutations in nuclear encoded mitochondrial enzymes. Furthermore, there is evidence that oncometabolites can affect mitochondrial dynamics. It is believed that oncometabolites can assist in reprogramming enzymatic pathways and providing cancer cells with selective advantages. In this review, we will touch upon the effects of normal and aberrant mitochondrial metabolism in normal and cancer cells, the advantages of metabolic reprogramming, effects of oncometabolites on metabolism and mitochondrial dynamics and therapies aimed at targeting oncometabolites and metabolic aberrations.

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“…All inhibitors were found to be competitive against α-KG, not NADPH and were inactive against the wildtype IDH1 homodimers. Interestingly, one of the inhibitors, EXEL-9324 (Compound 8 ), was found to inhibit the enzymatic activity of IDH1 heterodimer ( Wt / Mt ) but not the Wt / Wt homodimer [ 140 ].…”

Section: Therapeutic Avenuesmentioning

confidence: 99%

Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies

Madala

Punganuru

Arutla

et al. 2018

Cancers

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Isocitrate dehydrogenases 1 and 2 (IDH1,2), the key Krebs cycle enzymes that generate NADPH reducing equivalents, undergo heterozygous mutations in >70% of low- to mid-grade gliomas and ~20% of acute myeloid leukemias (AMLs) and gain an unusual new activity of reducing the α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2HG) in a NADPH-consuming reaction. The oncometabolite D-2HG, which accumulates >35 mM, is widely accepted to drive a progressive oncogenesis besides exacerbating the already increased oxidative stress in these cancers. More importantly, D-2HG competes with α-KG and inhibits a large number of α-KG-dependent dioxygenases such as TET (Ten-eleven translocation), JmjC domain-containing KDMs (histone lysine demethylases), and the ALKBH DNA repair proteins that ultimately lead to hypermethylation of the CpG islands in the genome. The resulting CpG Island Methylator Phenotype (CIMP) accounts for major gene expression changes including the silencing of the MGMT (O6-methylguanine DNA methyltransferase) repair protein in gliomas. Glioma patients with IDH1 mutations also show better therapeutic responses and longer survival, the reasons for which are yet unclear. There has been a great surge in drug discovery for curtailing the mutant IDH activities, and arresting tumor proliferation; however, given the unique and chronic metabolic effects of D-2HG, the promise of these compounds for glioma treatment is uncertain. This comprehensive review discusses the biology, current drug design and opportunities for improved therapies through exploitable synthetic lethality pathways, and an intriguing oncometabolite-inspired strategy for primary glioblastoma.

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AG-221, an Oral, Selective, First-in-Class, Potent IDH2-R140Q Mutant Inhibitor, Induces Differentiation in a Xenotransplant Model

Cited by 19 publications

References 0 publications

Consequences of IDH1/2 Mutations in Gliomas and an Assessment of Inhibitors Targeting Mutated IDH Proteins

Consequences of IDH1/2 Mutations in Gliomas and an Assessment of Inhibitors Targeting Mutated IDH Proteins

Metabolic Alterations in Cancer Cells and the Emerging Role of Oncometabolites as Drivers of Neoplastic Change

Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies

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