DISCOVERY OF IN VIVO CHEMICAL PROBES FOR POLYCOMB CBX DOMAINS
Polycomb CBX 域体内化学探针的发现
基本信息
- 批准号:9907857
- 负责人:
- 金额:$ 52.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-04-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityBindingBiologicalBiological AssayBiologyCalorimetryCancer ModelCell Membrane PermeabilityCell modelCellsChemicalsChromatinClinicalCommunitiesComplexDNADataData AnalysesDevelopmentDiseaseDrug Delivery SystemsDrug DesignDrug KineticsEZH2 geneEngineeringEnsureEukaryotaEvaluationGenerationsGenomeHistone H3HistonesHumanInterventionLigandsLysineMaintenanceMalignant NeoplasmsMalignant neoplasm of ovaryMalignant neoplasm of prostateMusMutateOncogenesOncologyPRC1 ProteinPathway interactionsPermeabilityPharmacologyPhase II Clinical TrialsPhenocopyPolycombPost-Translational Protein ProcessingPre-Clinical ModelPropertyProteinsPublishingRNAReaderReadingRegulationReportingRepressionResearchResistanceSeriesStructureSurface Plasmon ResonanceSystemTherapeuticTimeTitrationsToxic effectTransferaseUrsidae FamilyValidationWritingXenograft Modelanalogbasedrug candidateembryonic stem cellgenomic locusheterochromatin-specific nonhistone chromosomal protein HP-1histone modificationimprovedin vivointerestnovelnovel therapeuticsphysical propertypotency testingpre-clinicalprogramsprostate cancer cellprotein protein interactionrecruitresidencetargeted agenttherapeutic evaluationtooltumor
项目摘要
Chromatin is the complex of histone proteins, RNA, and DNA that efficiently packages the genome within
each human cell. The regulation of chromatin accessibility via post-translational modifications (PTM) of histones
is of great current interest as opportunities for pharmacological intervention in the ‘writing’, ‘reading’ and ‘erasing’
of these PTMs are significant. The biological consequences of most PTMs result from their recruitment of
regulatory machinery via protein-protein interactions directly facilitated by the PTM. The binding domains
involved in PTM recognition on chromatin are referred to as “readers”.
The overarching objective of this program is to develop an in vivo chemical probe of the CBX reader
domains of Polycomb repressive complex 1 (PRC1). There are eight human CBX chromodomains that function
as methyl-lysine (Kme) recognition domains (readers) within the two major chromatin repressive complexes that
are conserved across higher eukaryotes. CBX proteins 1, 3 and 5 are associated with the heterochromatin
protein 1 (HP1) complex. Their Kme binding activity is required for compaction and repression of chromatin that
bears the histone H3, lysine 9 trimethyl (H3K9me3) mark. CBX proteins 2, 4, 6, 7, and 8 are associated with the
PRC1 which binds the H3K27me3 mark. As appropriate repression of genomic loci is critical throughout
organismal development and differentiation, dysregulation of HP1 and Polycomb pathways is implicated in many
disease states and an in vivo chemical probe targeting PRC1 would be a first-in-class agent targeting a pathway
of high disease relevance and would also represent a unique tool to explore Polycomb biology in complex in vivo
systems.
The deliverable from this effort will be a high-quality in vivo chemical probe, freely available to the
academic community, with confirmed activity and well characterized mechanism versus the CBX readers of
PRC1 to catalyze progression of this target toward new therapeutic discoveries in oncology and, potentially,
other diseases.
染色质是组蛋白、RNA和DNA的复合物,其有效地将基因组包装在其中。
每个人体细胞通过组蛋白的翻译后修饰(PTM)调节染色质可及性
作为药物干预“写”、“阅读”和“擦除”的机会,
这些PTM都是重要的。大多数PTM的生物学后果是由于它们招募了
通过PTM直接促进的蛋白质-蛋白质相互作用调节机制。的结合结构域
参与染色质上的PTM识别的人被称为“读者”。
该计划的首要目标是开发CBX阅读器的体内化学探针
Polycomb repressive complex 1(PRC1)有八个人CBX染色体结构域,
作为两种主要染色质抑制复合物内的甲基赖氨酸(Kme)识别结构域(阅读器),
在高等真核生物中是保守的。CBX蛋白1、3和5与异染色质相关
蛋白1(HP 1)复合物。它们的Kme结合活性是染色质的压实和抑制所必需的,
带有组蛋白H3,赖氨酸9三甲基(H3 K9 me 3)标记。CBX蛋白2、4、6、7和8与
PRC 1结合H3 K27 me 3标记。在整个过程中,基因组位点的适当抑制至关重要
生物体发育和分化,HP 1和Polycomb途径的失调涉及许多
疾病状态和靶向PRC 1的体内化学探针将是靶向通路的一流试剂
具有高度的疾病相关性,也将代表一种独特的工具,以探索复杂的体内Polycomb生物学
系统.
这项工作的成果将是一种高质量的体内化学探针,
学术界,与CBX读者相比,
PRC 1催化该靶点向肿瘤学新治疗发现的进展,
其它疾病
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Stephen Vernon Frye其他文献
Stephen Vernon Frye的其他文献
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{{ truncateString('Stephen Vernon Frye', 18)}}的其他基金
PROBING ALLOSTERY IN METHYL-LYSINE READER DOMAINS
探索甲基赖氨酸阅读器结构域中的变构
- 批准号:
10369586 - 财政年份:2021
- 资助金额:
$ 52.06万 - 项目类别:
PROBING ALLOSTERY IN METHYL-LYSINE READER DOMAINS
探索甲基赖氨酸阅读器结构域中的变构
- 批准号:
10558469 - 财政年份:2021
- 资助金额:
$ 52.06万 - 项目类别:
Development of Small Molecules that Enhance the Delivery and the Pharmacological Effects of Oligonucleotides
开发增强寡核苷酸递送和药理作用的小分子
- 批准号:
8980120 - 财政年份:2015
- 资助金额:
$ 52.06万 - 项目类别:
DISCOVERY OF CHEMICAL PROBES FOR METHYL-LYSINE READERS
甲基赖氨酸读数器化学探针的发现
- 批准号:
8460807 - 财政年份:2012
- 资助金额:
$ 52.06万 - 项目类别:
DISCOVERY OF CHEMICAL PROBES FOR METHYL-LYSINE READERS
甲基赖氨酸读数器化学探针的发现
- 批准号:
8270684 - 财政年份:2012
- 资助金额:
$ 52.06万 - 项目类别:
Discovery of Small Molecule MBT Domain Antagonists
小分子 MBT 结构域拮抗剂的发现
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7943037 - 财政年份:2009
- 资助金额:
$ 52.06万 - 项目类别:
Discovery of Small Molecule MBT Domain Antagonists
小分子 MBT 结构域拮抗剂的发现
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7812717 - 财政年份:2009
- 资助金额:
$ 52.06万 - 项目类别:
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