Split-luciferase Epigenetic Assays for Drug Discovery
用于药物发现的分裂荧光素酶表观遗传学分析
基本信息
- 批准号:10482555
- 负责人:
- 金额:$ 24.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcademiaAddressArchitectureBindingBiological AssayBiologyBrain DiseasesBromodomainCellsChemicalsChromatinClinical TrialsComplexCoupledDNADNA Modification ProcessDataDeacetylaseDevelopmentDihydrofolate ReductaseDimerizationDoseEZH2 geneEnvironmentEnzymesEpigenetic ProcessEscherichia coliGene Expression RegulationGenerationsGenetic TranscriptionHistone DeacetylaseHistone-Lysine N-MethyltransferaseHistonesHuman GenomeHybridsIndustryInflammatoryLeadLuciferasesLysineMalignant NeoplasmsMalignant neoplasm of brainMeasurementMediatingMethylationMethyltransferaseModificationNatureNucleosomesPathway interactionsPatientsPermeabilityPharmaceutical PreparationsPharmacologic SubstancePharmacologyPhasePhenotypePhosphotransferasesPost-Translational Protein ProcessingProcessProteinsReaderRegulationReportingResearch PersonnelScaffolding ProteinSignal TransductionSiteSystemTailTechnologyTertiary Protein StructureToxic effectTranscriptional ActivationTransferaseValidationWritingassay developmentbasecandidate identificationchemical additioncostdesigndrug discoveryeffective therapyepigenomefeasibility testinggene repressionhistone acetyltransferasehistone methyltransferasehistone modificationin vitro Assayinhibitorinnovationinterestlead candidateluminescencenervous system disordernovel therapeuticsresponsesuccesstherapeutic candidatewound
项目摘要
Project Summary
Epigenetic control is essential for maintaining transcriptional integrity. Regulation of the dynamic
epigenome is mediated through a range of post translational modifications on DNA and histone
tails. Histone modifications are mediated by enzymes which can be broadly classified into “writers”
that catalyze the addition of chemical modifications, “erasers” that remove the modifications, and
“readers” that can recognize chemical modifications through specific protein domains. The writing
and erasing of histone marks by enzymes is a dynamic process, and when dysregulated is
associated with cancer, inflammatory and neurological diseases.
In this application we focus on the two classes of histone modifying enzymes, lysine methyl
transferases (KMTs) and lysine demethylases (KDMs), and aim to develop and validate cell-
based assays targeting both KMTs and KDMs. These assays, based on a three-hybrid split
luciferase system, are reversible allowing dose dependent quantification of inhibitor binding.
These efforts are both significant and innovative as they can report on the direct binding of a drug
to the target protein at its intended site of action, thereby facilitating the generation of lead
therapeutic candidates and identification of chemical probes for studying histone biology and
pathways.
项目摘要
表观遗传控制对于保持转录的完整性是必不可少的。对动态的调节
表观基因组是通过DNA和组蛋白上的一系列翻译后修饰来调节的
反面。组蛋白修饰是由酶介导的,这些酶可以广泛地分为“编写者”。
它催化了化学修饰的添加,移除了修饰的“橡皮”,以及
通过特定的蛋白质结构域识别化学修饰的“阅读器”。写作
而酶清除组蛋白标记是一个动态的过程,当失调时,
与癌症、炎症性疾病和神经系统疾病有关。
在本应用中,我们重点介绍了两类组蛋白修饰酶,即甲基赖氨酸
转移酶(KMT)和赖氨酸去甲基酶(KDM),旨在开发和验证细胞-
以KMT和KDM为目标的检测。这些化验是基于三杂交分裂
荧光素酶系统,是可逆的,允许抑制物结合的剂量依赖的定量。
这些努力是重要的和创新的,因为它们可以报告药物的直接结合
与目标蛋白在其预定的作用部位结合,从而促进铅的产生
用于研究组蛋白生物学和分子生物学的候选药物和化学探针的鉴定
小路。
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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{{ truncateString('REENA ZUTSHI', 18)}}的其他基金
Enabling Toxoplasma gondii Kinome Directed Drug Discovery
实现弓形虫激酶组定向药物发现
- 批准号:
10602259 - 财政年份:2019
- 资助金额:
$ 24.04万 - 项目类别:
Tools for Accelerating R&D for Historically Understudied Protein Kinases
加速 R 的工具
- 批准号:
9264156 - 财政年份:2017
- 资助金额:
$ 24.04万 - 项目类别:
Enabling Malarial Kinome Directed Drug Discovery
实现疟疾激酶组定向药物发现
- 批准号:
8714538 - 财政年份:2014
- 资助金额:
$ 24.04万 - 项目类别:
A Poly(ADP-Ribose) Detection Assay Enabling Drug Discovery and Development
聚 (ADP-核糖) 检测分析促进药物发现和开发
- 批准号:
8123053 - 财政年份:2011
- 资助金额:
$ 24.04万 - 项目类别:
Rapid Kinase Profiling with Luminescent Reporters
使用发光报告基因快速分析激酶
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8005176 - 财政年份:2010
- 资助金额:
$ 24.04万 - 项目类别:
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使用发光报告基因快速分析激酶
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7745380 - 财政年份:2009
- 资助金额:
$ 24.04万 - 项目类别:
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