Novel Therapeutic Agents for Gliomas with IDH Mutations

描述（由申请人提供）：最近的一项全基因组分析显示，大约80%的II-III级胶质瘤和继发性胶质母细胞瘤在细胞质异柠檬酸脱氢酶1 （IDH1）中存在突变。随后的研究表明，突变体IDH1获得了一种新的功能，将α -酮戊二酸转化为2-羟基戊二酸。因此，野生型IDH1产生的α -酮戊二酸被突变型IDH1消耗，耗尽细胞中的α -酮戊二酸。我们假设IDH1突变的细胞可能更容易被谷氨酰胺溶解阻断，谷氨酰胺溶解作为α -酮戊二酸的替代来源，在肿瘤细胞的增殖中起着关键作用。为了验证这一假设，将追求以下目标：目标1。)鉴定具有改进的类药物分子特性的有效可溶性GLS抑制剂；目标2。)评估GLS抑制剂对D54胶质母细胞瘤细胞系的抗增殖作用。在本项目完成后，我们期望能够鉴定出具有更多类似药物分子特性的GLS抑制剂，作为治疗原型，在未来的神经胶质瘤动物模型中建立体内概念验证。

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.