Histone Lysine deMethylation: Structures, Inhibitions and Mechanisms

组蛋白赖氨酸去甲基化：结构、抑制和机制

基本信息

批准号：
9039106
负责人：
Xiaodong Cheng
金额：
$ 28.87万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9039106
关键词：
ARID Domain Adult Aromatic Compounds Bacteria Binding Cells Characteristics Chemopreventive Agent Chromatin Cleaved cell Clinical Complex DNA DNA Methylation Data Development Dioxygenases Disease Progression Disease model Drosophila genus Enzymes Epigenetic Process Event Exhibits FDA approved Family Family member Flavones Flavonoids Gene Expression Gene Mutation Genes Genistein Genome Stability Goals Health Histone Acetylation Histone Code Histone Deacetylase Histone H3 Histone-Lysine N-Methyltransferase Histones Human Huntington Disease Huntington gene In Vitro Individual Isoflavones Kinetics Lead Link Luteolin Lysine Malignant Neoplasms Malignant neoplasm of prostate Mammalian Cell Methylation Methyltransferase Modification Molecular Mus N-terminal Natural Products Nature Neurons PHD Finger Patients Peptides Pharmacologic Substance Phase II Clinical Trials Play Preclinical Testing Prostatectomy Protein Family Proteins Reagent Renal carcinoma Role Sampling Somatic Mutation Source Structure Therapeutic Intervention Toxic effect Transcriptional Activation Validation X Chromosome X-Linked Mental Retardation analog baicalein base cancer cell chromatin modification chromosome mutation cofactor daidzein demethylation design epigenetic regulation epigenome gene repression histone demethylase histone methylation histone methyltransferase human disease improved in vivo inhibitor/antagonist leukemia treatment methylation pattern mutant outcome forecast overexpression programs small molecule small molecule inhibitor soy protein isolate therapeutic target tumor progression

项目摘要

DESCRIPTION (provided by applicant): Epigenetic regulation constitutes a fundamentally important set of gene control mechanisms that profoundly influence chromatin function, with direct relevance to a large number of human diseases. Histone lysine methylation and demethylation are components of a "histone code", and the recognition of these methyl marks underlies epigenetic regulation. For example, overexpression of a histone lysine demethylase, PHF8, has been noted in primary prostate cancer samples, where it is associated with increased invasiveness and a poorer prognosis. The inherently reversible nature of epigenetic modifications makes enzymes that modify histones and DNA attractive candidates for therapeutic intervention. Thus far such epigenetic therapies have focused on the enzymes that regulate histone acetylation and DNA methylation, with several HDAC and DNMT inhibitors now in clinical use and FDA approved for the treatment of leukemias and other cancers. The enzymes involved in regulating histone methylation patterns and levels have emerged as highly promising therapeutic targets, with newer histone methyltransferase inhibitors recently entering preclinical testing. Histone lysine demethylases (belong to a broad family of non-heme Fe(II)-dependent dioxygenases), on the other hand, remain a relatively untapped source of potential "druggable targets". The central goal of this proposal is to validate, re-design, and synthesize small molecule inhibitors of histone lysine demethylases in vitro, and to investigate the mechanism(s) of inhibition by nature (iso)flavone derivatives.

描述（应用程序提供）：表观遗传调节构成了一组重要的基因控制机制，这些机制深远影响染色质功能，与大量人类疾病直接相关。组蛋白赖氨酸甲基化和脱甲基化是“组蛋白代码”的成分，这些甲基标记的识别是表观遗传调节的基础。例如，在原发性前列腺癌样品中已经注意到了组蛋白赖氨酸脱甲基酶PHF8的过表达，在该样品中，它与浸润性增加和预后较差有关。表观遗传修饰的固有可逆性使得修饰组蛋白和DNA有吸引力的治疗干预的酶。这种表观遗传疗法的重点是调节组蛋白乙酰化和DNA甲基化的酶，现在在临床用途中使用了几种HDAC和DNMT抑制剂，并批准FDA用于治疗白血病和其他癌症。涉及控制组蛋白甲基化模式和水平的酶已成为高度有前途的治疗靶标，而新的组蛋白甲基转移酶抑制剂最近进入临床前测试。另一方面，组蛋白赖氨酸脱甲基酶（属于非血红素Fe（II）依赖性二加氧酶的广泛家族）仍然是相对未开发的潜在“可药靶”的来源。该提案的核心目的是在体外验证，重新设计和合成组蛋白赖氨酸脱甲基酶的小分子抑制剂，并研究自然界抑制（ISO）黄酮衍生物的机制。