Novel Therapeutic Agents for Gliomas with IDH Mutations

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DESCRIPTION (provided by applicant): A recent genome wide analysis revealed that approximately 80% of grade II-III gliomas and secondary glioblasotomas harbor mutations in cytosolic isocitrate dehydrogenase 1 (IDH1). Subsequent studies revealed that the mutant IDH1 gained a new function, conversion of alpha- ketoglutarate to 2-hydroxyglutarate. Thus, alpha-ketoglutarate produced by wild-type IDH1 is consumed by the mutant IDH1, depleting cells of alpha-ketoglutarate. We hypothesized that cells with mutant IDH1 may be more susceptible to blockade of glutaminolysis, which plays a critical role in proliferation of tumor cells by serving as an alternative source of alpha-ketoglutarate. To test this hypothesis, the following aims will be pursued: Aim 1.) Identify potent soluble GLS inhibitors with improved drug-like molecular properties; Aim 2.) Assess antiproliferative effects of GLS inhibitors in D54 glioblastoma cell lines. Upon completion of this project, we expect to identify new GLS inhibitors with more drug-like molecular properties, which can serve as therapeutic prototypes to establish in vivo proof-of-concept in animal models of glioma in future. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to conduct systematic SAR (structure-activity relationships) studies to identify kidney-type glutaminase (GLS) inhibitors as small molecule probes for evaluating the therapeutic utility of GLS inhibition in glioma with IDH (isocitrate dehydrogenase) mutations. New GLS inhibitors emerging from this project will be tested in comparative cell growth studies using D54 glioblastoma cell lines constitutively overexpressing either wild-type or mutant R132H IDH1. These studies should lead to the discovery of new GLS inhibitors with more drug-like properties, which can serve as therapeutic prototypes in future experiments to establish in vivo proof-of-concept in animal models of glioma.