Novel Therapeutic Agents for Gliomas with IDH Mutations

描述（由申请人提供）：最近的全基因组分析显示，约80%的II-III级胶质瘤和继发性胶质母细胞瘤在胞质异柠檬酸脱氢酶1（IDH 1）中存在突变。随后的研究表明，突变体IDH 1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，由野生型IDH 1产生的α-酮戊二酸被突变体IDH 1消耗，耗尽细胞的α-酮戊二酸。我们假设具有突变IDH 1的细胞可能更容易阻断β-氨基酮分解，β-氨基酮分解通过作为α-酮戊二酸的替代来源在肿瘤细胞增殖中起关键作用。为了检验这一假设，将追求以下目标：目标1。鉴定具有改善的药物样分子性质的有效可溶性GLS抑制剂;目的2.）评估GLS抑制剂在D54胶质母细胞瘤细胞系中的抗增殖作用。在完成该项目后，我们期望鉴定出具有更多药物样分子特性的新GLS抑制剂，其可以作为治疗原型，以在未来的胶质瘤动物模型中建立体内概念验证。 公共卫生相关性：拟议研究的目标是进行系统的SAR（构效关系）研究，以确定肾型转氨酶（GLS）抑制剂作为小分子探针，用于评估GLS抑制在IDH（异柠檬酸脱氢酶）突变的胶质瘤中的治疗效用。将在比较细胞生长研究中使用组成型过表达野生型或突变型R132 H IDH 1的D54胶质母细胞瘤细胞系测试从该项目中出现的新GLS抑制剂。这些研究应该会导致发现新的GLS抑制剂具有更多的药物样特性，这可以作为治疗原型在未来的实验中建立体内概念验证的神经胶质瘤动物模型。

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.