Chemical Probes Targeting Gliomas with IDH Mutation

针对 IDH 突变神经胶质瘤的化学探针

基本信息

批准号：
8925163
负责人：
Yongcheng Song
金额：
$ 34.3万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8925163
关键词：
Acids Age Apoptosis Autophagocytosis Binding Biochemical Biological Biological Process Biological Testing Brain Neoplasms Cells Cellular biology Cerebrum Chemicals Citric Acid Cycle Complex Crystallography Cytosol DNA Methylation DNA Sequence Drug Kinetics Drug Targeting Enzymes Event Exhibits Genetic Germ-Line Mutation Glioblastoma Glioma Growth Health High Pressure Liquid Chromatography Histones Human Intervention Investigation Isocitrate Dehydrogenase Isocitrates Lead Malignant neoplasm of brain Measures Metabolism Methods Mitochondria Molecular Biology Mus Mutation NADP Neuraxis Normal Cell Patients Pharmaceutical Chemistry Pharmaceutical Preparations Play Primary Neoplasm Property Proteins Quantitative Structure-Activity Relationship RNA Interference Research Risk Roentgen Rays Role Structure Structure-Activity Relationship Testing Therapeutic Time Toxic effect X-Ray Crystallography Xenograft Model Xenograft procedure absorption cancer type clinically relevant cofactor counterscreen cytotoxicity design improved in vitro activity in vitro testing in vivo inhibitor/antagonist isocitrate knock-down mouse model mutant neoplastic cell nervous system disorder novel screening tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Isocitrate dehydrogenase (IDH) is one of the key enzymes in the tricarboxylic acid cycle, catalyzing the conversion of isocitric acid to α-ketoglutaric acid (α-KG) using NADP+. DNA sequencing of a large number of human gilomas has revealed that ~75% of low - medium grade gliomas and secondary glioblastoma multiforme (GBM, a highly lethal form of brain tumor) carry IDH mutations, with IDH1 R132H mutation being predominant (~90%). Genetic investigations have found that IDH mutations are always heterozygous, suggesting the wild-type enzyme is essential for both normal and tumor cells, and IDH mutation is an early and critical event in the glioma tumorigenesis. Biochemical characterization of the mutant proteins revealed that they are inactive in converting isocitrate to α-KG. Rather, all of the mutant proteins, e.g., IDH1(R132H), possess a new enzymatic activity: they catalyze the reduction of α-KG to D-2-hydroxyglutaric acid (2-HG) using NADPH. This neo-function is responsible for the greatly elevated (>100x) level of 2-HG in primary tumor cells bearing IDH mutations. Growing evidence strongly supports 2-HG is an onco-metabolite and mutant IDH a target for intervention. Although it is clear that a high level of 2-HG is very harmfu to human health (especially central nervous system), whether inhibition of mutant IDH blocks the growth or induces apoptosis of this type of tumor cells remains to be answered. This is because there have been no inhibitors of mutant IDH to date. In addition, RNA interference (RNAi) is not appropriate for this study, since it will also knock down the wild-type IDH enzyme, whose function is essential for both normal and tumor cells. The first Specific Aim is to use medicinal chemistry, protein X-ray crystallography and quantitative structure activity relationship (QSAR) to develop potent and selective inhibitors of IDH1(R132H). The second Specific Aim is to test in vitro biological activities of compounds synthesized in Aim 1 as well as pharmacokinetic and toxicological properties of selected compounds. The third Specific Aim is to determine the in vivo antitumor activity of our potent IDH1(R132H) inhibitors in intra-cerebral xenograft mouse models as well as to use molecular and cell biology methods to identify the mechanisms of action of these novel inhibitors.

描述（由应用提供）：异氯酸酯脱氢酶（IDH）是三核酸周期中的关键酶之一，使用NADP+催化异凝酸向α-酮戊二酸（α-kg）的转化。大量人类gilomas的DNA测序表明，约有75％的低中级神经胶质瘤和继发性胶质母细胞瘤多形（GBM，一种高度致命的脑肿瘤形式）携带IDH突变，而IDH1 R132H突变主要为主导（〜90％）。遗传研究发现，IDH突变始终是杂合的，这表明野生型酶对正常和肿瘤细胞都是必不可少的，而IDH突变是神经胶质瘤肿瘤发生的早期和关键事件。突变蛋白的生化表征表明，它们在将等异急塞转化为α-kg时不活跃。相反，所有突变蛋白，例如IDH1（R132H）都具有新的酶促活性：它们使用NADPH催化α-KG将α-KG还原为D-2-羟基谷物（2-Hg）。该新功能负责带有IDH突变的原发性肿瘤细胞中2-Hg的高度升高（> 100倍）。越来越多的证据强烈支持2-HG是一种onco-亚代谢物，而突变体IDH是干预措施的目标。尽管很明显，高水平的2-HG对人类健康非常有害（尤其是中枢神经系统），但是否抑制突变体IDH会阻止生长还是诱导这种类型的肿瘤细胞凋亡。这是因为迄今为止尚无突变体IDH的抑制剂。此外，RNA干扰（RNAI）不适合这项研究，因为它还将拆除野生型IDH酶，其功能对于正常细胞和肿瘤细胞都是必不可少的。第一个具体目的是使用医学化学，蛋白质X射线晶体学和定量结构活性关系（QSAR）来开发IDH1（R132H）的潜在和选择性抑制剂。第二个具体目的是测试AIM 1中合成的化合物的体外生物学活性以及所选化合物的药代动力学和毒理学特性。第三个具体目的是确定我们潜在的IDH1（R132H）抑制剂在脑外壳移植小鼠模型中的体内抗肿瘤活性，以及使用分子和细胞生物学方法来识别这些新型抑制剂的作用机理。