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</script>pmid: 28124097
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.
Mice, Inbred BALB C, Aniline Compounds, Brain Neoplasms, Cell Survival, Mice, Nude, Antineoplastic Agents, Astrocytoma, Isocitrate Dehydrogenase, Recombinant Proteins, Glutarates, HEK293 Cells, Cell Line, Tumor, Colonic Neoplasms, Mutation, Escherichia coli, Animals, Humans, Benzimidazoles, Female, Enzyme Inhibitors
Mice, Inbred BALB C, Aniline Compounds, Brain Neoplasms, Cell Survival, Mice, Nude, Antineoplastic Agents, Astrocytoma, Isocitrate Dehydrogenase, Recombinant Proteins, Glutarates, HEK293 Cells, Cell Line, Tumor, Colonic Neoplasms, Mutation, Escherichia coli, Animals, Humans, Benzimidazoles, Female, Enzyme Inhibitors
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| influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically). | Top 10% | |
| impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network. | Top 1% |
