Abstract
Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia. We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ2-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model, after a single oral dose of 30 mg/kg, 16 h post dose, between 16 and 48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Brain / metabolism
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Cell Line, Tumor
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Drug Evaluation, Preclinical
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / therapeutic use
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Female
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Glycine / analogs & derivatives
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Glycine / therapeutic use
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Half-Life
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Humans
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Isocitrate Dehydrogenase / antagonists & inhibitors*
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Isocitrate Dehydrogenase / genetics
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Isocitrate Dehydrogenase / metabolism
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Mice
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Mice, Nude
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Microsomes, Liver / metabolism
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Mutagenesis, Site-Directed
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Neoplasms / drug therapy
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Neoplasms / pathology
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Pyridines / therapeutic use
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Pyridones / chemistry*
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Pyridones / metabolism
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Pyridones / therapeutic use
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Rats
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Enzyme Inhibitors
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Pyridines
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Pyridones
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Isocitrate Dehydrogenase
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IDH1 protein, human
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ivosidenib
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Glycine