权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9136239
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 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9136239
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 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（申请人提供）：异柠檬酸脱氢酶（IDH）是三羧酸循环中的关键酶之一，利用NADP+催化异柠檬酸转化为α-酮戊二酸（α-KG）。对大量人类胶质瘤的 DNA 测序显示，约 75% 的低-中度胶质瘤和继发性多形性胶质母细胞瘤（GBM，一种高度致命的脑肿瘤）携带 IDH 突变，其中 IDH1 R132H 突变占主导地位（约 90%）。遗传学研究发现IDH突变总是杂合的，这表明野生型酶对于正常细胞和肿瘤细胞都是必需的，并且IDH突变是神经胶质瘤发生的早期和关键事件。突变蛋白的生化特征表明它们在将异柠檬酸转化为 α-KG 方面没有活性。相反，所有突变蛋白，例如 IDH1(R132H)，都具有新的酶活性：它们利用 NADPH 催化 α-KG 还原为 D-2-羟基戊二酸 (2-HG)。这种新功能导致携带 IDH 突变的原发性肿瘤细胞中 2-HG 水平大幅升高（>100 倍）。越来越多的证据强烈支持 2-HG 是一种肿瘤代谢物，而突变 IDH 是干预的目标。尽管已经明确高水平的2-HG对人类健康（尤其是中枢神经系统）非常有害，但抑制突变IDH是否会阻止此类肿瘤细胞的生长或诱导其凋亡仍有待解答。这是因为迄今为止还没有突变 IDH 的抑制剂。此外，RNA 干扰 (RNAi) 不适用于本研究，因为它还会敲低野生型 IDH 酶，而该酶的功能对于正常细胞和肿瘤细胞都至关重要。第一个具体目标是利用药物化学、蛋白质X射线晶体学和定量结构活性关系（QSAR）来开发IDH1（R132H）的有效和选择性抑制剂。第二个具体目标是测试目标 1 中合成的化合物的体外生物活性以及所选化合物的药代动力学和毒理学特性。第三个具体目标是确定我们的有效 IDH1(R132H) 抑制剂在脑内异种移植小鼠模型中的体内抗肿瘤活性，并使用分子和细胞生物学方法来确定这些新型抑制剂的作用机制。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Inhibition of Mutated Isocitrate Dehydrogenase 1 in Cancer.

抑制癌症中突变的异柠檬酸脱氢酶 1。

DOI：
10.2174/1573406414666180524093659
发表时间：
2018
期刊：
Medicinal chemistry (Shariqah (United Arab Emirates))
影响因子：
0
作者：
Wu,Fangrui;Cheng,Gang;Yao,Yuan;Kogiso,Mari;Jiang,Hong;Li,Xiao-Nan;Song,Yongcheng
通讯作者：
Song,Yongcheng

Synergistic anti-tumor efficacy of mutant isocitrate dehydrogenase 1 inhibitor SYC-435 with standard therapy in patient-derived xenograft mouse models of glioma.

DOI：
10.1016/j.tranon.2022.101368
发表时间：
2022-04
期刊：
Translational oncology
影响因子：
5
作者：
Kogiso M;Qi L;Du Y;Braun FK;Zhang H;Huang LF;Guo L;Huang Y;Teo WY;Lindsay H;Zhao S;Injac SG;Liu Z;Mehta V;Tran D;Li F;Baxter PA;Su JM;Perlaky L;Parsons DW;Chintagumpala M;Adesina A;Song Y;Li XN
通讯作者：
Li XN

Inhibition of Cancer-Associated Mutant Isocitrate Dehydrogenases by 2-Thiohydantoin Compounds.