Abstract
Mutations in codon 132 of isocitrate dehydrogenase (IDH) 1 are frequent in diffuse glioma, acute myeloid leukemia, chondrosarcoma and intrahepatic cholangiocarcinoma. These mutations result in a neomorphic enzyme specificity which leads to a dramatic increase of intracellular D-2-hydroxyglutarate (2-HG) in tumor cells. Therefore, mutant IDH1 protein is a highly attractive target for inhibitory drugs. Here, we describe the development and properties of BAY 1436032, a pan-inhibitor of IDH1 protein with different codon 132 mutations. BAY 1436032 strongly reduces 2-HG levels in cells carrying IDH1-R132H, -R132C, -R132G, -R132S and -R132L mutations. Cells not carrying IDH mutations were unaffected. BAY 1436032 did not exhibit toxicity in vitro or in vivo. The pharmacokinetic properties of BAY 1436032 allow for oral administration. In two independent experiments, BAY 1436032 has been shown to significantly prolong survival of mice intracerebrally transplanted with human astrocytoma carrying the IDH1R132H mutation. In conclusion, we developed a pan-inhibitor targeting tumors with different IDH1R132 mutations.
Keywords:
Drug development; IDH-mutated glioma; IDH1R132 inhibitor; Mouse xenograft; Pharmacology; Therapy.
MeSH terms
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Aniline Compounds / chemistry
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Aniline Compounds / pharmacokinetics
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Aniline Compounds / pharmacology*
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Aniline Compounds / toxicity
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / toxicity
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Astrocytoma / drug therapy*
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Astrocytoma / enzymology
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Astrocytoma / genetics
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Benzimidazoles / chemistry
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology*
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Benzimidazoles / toxicity
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / enzymology
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Brain Neoplasms / genetics
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / physiology
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Colonic Neoplasms / drug therapy
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Colonic Neoplasms / enzymology
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Colonic Neoplasms / genetics
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / toxicity
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Escherichia coli
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Female
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Glutarates / metabolism
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HEK293 Cells
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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, Inbred BALB C
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Mice, Nude
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Mutation
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Sarcoma / drug therapy
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Sarcoma / enzymology
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Sarcoma / genetics
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Sf9 Cells
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Xenograft Model Antitumor Assays
Substances
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Aniline Compounds
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Antineoplastic Agents
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BAY 1436032
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Benzimidazoles
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Enzyme Inhibitors
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Glutarates
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Recombinant Proteins
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alpha-hydroxyglutarate
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IDH2 protein, human
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Isocitrate Dehydrogenase
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IDH1 protein, human