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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：
8861037
负责人：
Xiaodong Cheng
金额：
$ 30.27万
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/8861037
关键词：
ARID Domain Adult Aromatic Compounds Bacteria Binding Biological Factors 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 Histone Acetylation Histone Code Histone Deacetylase Histone H3 Histone-Lysine N-Methyltransferase Histones Human Huntington Disease In Vitro Individual Inhibitory Concentration 50 Isoflavones Kinetics Lead Link Luteolin Lysine Malignant Neoplasms Malignant neoplasm of prostate Mammalian Cell Methylation Methyltransferase Modification Molecular Mus N-terminal 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 Huntingtin protein human disease improved in vivo inhibitor/antagonist leukemia treatment methylation pattern mutant outcome forecast overexpression programs public health relevance small molecule 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.