agi-5198 has been researched along with Cell-Transformation--Neoplastic* in 3 studies
3 other study(ies) available for agi-5198 and Cell-Transformation--Neoplastic
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Rapid Conversion of Mutant IDH1 from Driver to Passenger in a Model of Human Gliomagenesis.
Missense mutations in the active site of isocitrate dehydrogenase 1 (IDH1) biologically and diagnostically distinguish low-grade gliomas and secondary glioblastomas from primary glioblastomas. IDH1 mutations lead to the formation of the oncometabolite 2-hydroxyglutarate (2-HG) from the reduction of α-ketoglutarate (α-KG), which in turn facilitates tumorigenesis by modifying DNA and histone methylation as well blocking differentiation processes. Although mutant IDH1 expression is thought to drive the gliomagenesis process, the extent to which it remains a viable therapeutic target remains unknown. To address this question, we exposed immortalized (p53/pRb deficient), untransformed human astrocytes to the mutant IDH1 inhibitor AGI-5198 prior to, concomitant with, or at intervals after, introduction of transforming mutant IDH1, then measured effects on 2-HG levels, histone methylation (H3K4me3, H3K9me2, H3K9me3, or H3K27me3), and growth in soft agar. Addition of AGI-5198 prior to, or concomitant with, introduction of mutant IDH1 blocked all mutant IDH1-driven changes, including cellular transformation. Addition at time intervals as short as 4 days following introduction of mutant IDH1 also suppressed 2-HG levels, but had minimal effects on histone methylation, and lost the ability to suppress clonogenicity in a time-dependent manner. Furthermore, in two different models of mutant IDH1-driven gliomagenesis, AGI-5198 exposures that abolished production of 2-HG also failed to decrease histone methylation, adherent cell growth, or anchorage-independent growth in soft agar over a prolonged period. These studies show although mutant IDH1 expression drives gliomagenesis, mutant IDH1 itself rapidly converts from driver to passenger.. Agents that target mutant IDH may be effective for a narrow time and may require further optimization or additional therapeutics in glioma. Mol Cancer Res; 14(10); 976-83. ©2016 AACR. Topics: Astrocytes; Benzeneacetamides; Brain Neoplasms; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Cells, Cultured; Glioma; Glutarates; Histones; Humans; Imidazoles; Isocitrate Dehydrogenase; Methylation; Mutation | 2016 |
An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells.
The recent discovery of mutations in metabolic enzymes has rekindled interest in harnessing the altered metabolism of cancer cells for cancer therapy. One potential drug target is isocitrate dehydrogenase 1 (IDH1), which is mutated in multiple human cancers. Here, we examine the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screen blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2-hydroxyglutarate (R-2HG). Under conditions of near-complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation. Blockade of mIDH1 impaired the growth of IDH1-mutant--but not IDH1-wild-type--glioma cells without appreciable changes in genome-wide DNA methylation. These data suggest that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects. Topics: Animals; Benzeneacetamides; Cell Differentiation; Cell Transformation, Neoplastic; Enzyme Inhibitors; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glioma; Glutarates; Histones; Imidazoles; Isocitrate Dehydrogenase; Methylation; Mice; Mice, SCID; Mutant Proteins; Protein Multimerization; RNA Interference; Xenograft Model Antitumor Assays | 2013 |
Cancer. Silencing a metabolic oncogene.
Topics: Animals; Benzeneacetamides; Cell Differentiation; Cell Transformation, Neoplastic; Enzyme Inhibitors; Glioma; Glutarates; Hematopoiesis; Humans; Imidazoles; Isocitrate Dehydrogenase; Leukemia; Leukemia, Myeloid, Acute; Phenylurea Compounds; Procollagen-Proline Dioxygenase; Sulfonamides | 2013 |