Novel Therapeutic Agents for Gliomas with IDH Mutations

描述(申请人提供)：最近的全基因组分析显示，大约80%的II-III级胶质瘤和继发性胶质母细胞瘤存在胞浆异柠檬酸脱氢酶1(IDH1)突变。随后的研究表明，突变的IDH1获得了一个新的功能，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-酮戊二酸被突变的IDH1消耗，消耗α-酮戊二酸的细胞。我们推测，突变IDH1的细胞可能更容易被谷氨酰胺分解阻断，谷氨酰胺分解通过作为α-酮戊二酸的替代来源在肿瘤细胞的增殖中发挥关键作用。为了验证这一假设，将追求以下目标：目标1。确定具有改进的类药物分子特性的有效的可溶性GLS抑制剂；目标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。该项目完成后，我们希望找到具有更多类药物分子特性的新的GLS抑制剂，这些药物可以作为治疗原型，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结构-活性关系(SAR)研究，以确定肾型谷氨酰胺酶(GLS)抑制剂作为小分子探针，用于评估GLS抑制对具有异柠檬酸脱氢酶(IDH)突变的胶质瘤的治疗作用。从该项目中出现的新的GLS抑制剂将在比较细胞生长研究中进行测试，使用D54胶质母细胞瘤细胞系，该细胞系结构性地过表达野生型或突变型R132H IDH1。这些研究应该会导致发现具有更多药物样特性的新的GLS抑制剂，这些药物可以在未来的实验中作为治疗原型，以建立在脑胶质瘤动物模型中的体内概念验证。

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.