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Non-nucleoside inhibitors of DNA methyl transferase I

DNA 甲基转移酶 I 非核苷抑制剂

基本信息

批准号：
8574469
负责人：
Nigel D PRIESTLEY
金额：
$ 41.04万
依托单位：
UNIVERSITY OF MONTANA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-05 至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8574469
关键词：
Anabolism Antineoplastic Agents Apoptosis Apoptotic Binding Biochemical Biological Assay Biological Factors Cancer cell line Cell Death Cell Line Cells Cessation of life Chemicals Chemotherapy-Oncologic Procedure Colorectal Cancer Combinatorial Synthesis Coupling CpG dinucleotide Cytosine DNA DNA Methylation DNA Methyltransferase DNA Modification Methylases DNA Modification Process DNA biosynthesis Data Development Dinucleotide Repeats Docking Drug Design Enzymes Epigenetic Process Equilibrium Evaluation Fluorouracil Gene Silencing Generations Genes Genomics Goals Human Human Cell Line Hybrids Hypermethylation In Vitro Investigation Laboratories Libraries Liver Microsomes MLH1 gene Maintenance Malignant Neoplasms Measurement Measures Methylation Methyltransferase Mitosis Modeling Pathway interactions Pharmaceutical Preparations Play Process Promoter Regions Proteins Radioactivity Reaction Refractory Role Site Stimulus Structure Synthesis Chemistry Therapeutic Therapeutic Agents Toxic effect Transferase Western Blotting analog base cancer cell chemotherapy combinatorial design drug candidate histone methyltransferase inhibitor/antagonist neoplastic cell novel novel therapeutics nucleoside inhibitor outcome forecast programs promoter public health relevance response scaffold screening tool tumor virtual

项目摘要

DESCRIPTION (provided by applicant): The acquisition of genomic alterations is a defining feature of human cancers. Cancer chemotherapy relies upon the cell death or apoptotic pathway to eradicate cells containing these alterations. The maintenance of appropriate methylation levels in DNA is necessary during normal DNA replication and mitosis. Disruption of correct and appropriate methylation leads to non-mutagenic changes associated with transcriptional silencing in tumor cells. Transcriptional silencing of genes along the apoptotic pathway abrogates the efficacy of chemotherapy and such tumors are refractory to classical therapy and associated with a poor prognosis. Epigenetic methylation of cytosine in DNA occurs at CpG sites in dense clusters of CpG dinucleotide repeats within gene promoters and is catalyzed by DNA methyl transferase enzymes (Dnmt's). Therapeutics that can inhibit Dnmt can reactivate genes silenced by hypermethylation, therefore, the design and development of novel Dnmt inhibitors is a worthy goal especially as the silenced genes remain intact and functional. We have constructed unique libraries of natural product derivatives based upon natural product isolation, combinatorial biosynthesis and parallel combinatorial synthesis. Our libraries are composed of structures that retain the topological and stereochemical complexity of natural products yet are straightforward to prepare. In screening our libraries against the human Dnmt-1 enzyme we discovered that compounds with an isoindolinone core scaffold were excellent inhibitors with Ki values as low as 20 micromolar. In this application we seek to demonstrate that we can develop potent and selective inhibitors of Dnmt-1. We further seek to demonstrate that our inhibitors cause reactivation of a model epigenetically silenced gene, human MLH1.

描述（由申请人提供）：基因组改变的获得是人类癌症的一个定义特征。癌症化疗依赖于细胞死亡或凋亡途径来根除含有这些改变的细胞。在正常的 DNA 复制和有丝分裂过程中，维持适当的 DNA 甲基化水平是必要的。正确和适当的甲基化的破坏会导致与肿瘤细胞转录沉默相关的非诱变变化。沿着细胞凋亡途径的基因转录沉默会消除化疗的功效，并且此类肿瘤对经典疗法难以治疗并且与不良预后相关。 DNA 中胞嘧啶的表观遗传甲基化发生在基因启动子内密集的 CpG 二核苷酸重复簇中的 CpG 位点，并由 DNA 甲基转移酶 (Dnmt's) 催化。能够抑制 Dnmt 的疗法可以重新激活因高甲基化而沉默的基因，因此，新型 Dnmt 抑制剂的设计和开发是一个有价值的目标，特别是在沉默的基因保持完整和功能的情况下。我们基于天然产物分离、组合生物合成和平行组合合成，构建了独特的天然产物衍生物库。我们的文库由保留天然产物的拓扑和立体化学复杂性但易于制备的结构组成。在针对人类 Dnmt-1 酶筛选我们的文库时，我们发现具有异吲哚酮核心支架的化合物是优异的抑制剂，Ki 值低至 20 微摩尔。在此应用中，我们试图证明我们可以开发有效且选择性的 Dnmt-1 抑制剂。我们进一步试图证明我们的抑制剂会导致表观遗传沉默模型基因（人类 MLH1）的重新激活。