Chemical Probes Targeting Polycomb Repressive Complex 2 Gene Repression

针对 Polycomb 抑制复合物 2 基因抑制的化学探针

基本信息

批准号：
8742117
负责人：
Guillermo Gerona-Navarro
金额：
$ 15.7万
依托单位：
BROOKLYN COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8742117
关键词：
Acute Myelocytic Leukemia Address Affinity Antineoplastic Agents Area B-Cell Lymphomas Binding Biochemical Biological Assay Biological Process Cancer Biology Cell physiology Cells Chemicals Chromatin Complex Computing Methodologies Development EZH2 gene Epigenetic Process Evaluation Funding Future Gene Expression Gene Targeting Genes Goals Grant Health Histone H3 Human Hyperactive behavior In Vitro Individual Knock-out Knowledge Label Lead Libraries Ligand Binding Ligands Link Literature Lysine MLL-AF9 Malignant Neoplasms Mammals Mediating Memory Methodology Methylation PRC1 Protein Peptides Phase Polycomb Protein Overexpression Proteins Reporting Repression Research Role SET Domain Solid Specificity Structure Synthesis Chemistry Testing Time Transcription Repressor/Corepressor Translating Tumor Suppressor Genes Zinc Fingers base biophysical techniques cancer therapy cell growth college design gene repression histone methyltransferase human disease in vivo inhibitor/antagonist insight interest leukemia member neoplastic novel outcome forecast peptidomimetics promoter public health relevance research study screening small molecule stem cell biology stem cell division tool tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Polycomb group proteins (PcG) are transcriptional repressors that bind the promoters of genes encoding proteins with key roles in cell fate determination in many cellular lineages. These proteins mediate their functions by silencing inappropriate expressions and maintaining a chromatin repressive state. PcG proteins are known to form large multimeric complexes of two general types, PRC1 and PRC2. PRC2 is involved in the initiation of gene repression and it has intrinsic histone methyltransferase activiy, with specificity for lysine 27 of histone H3 (H3K27), whereas PRC1 is important for effecting transcriptional repression. A large body of literature links PRC2 components EZH2, EED and SUZ12 to tumor genesis, poor prognosis and tumor proliferation. Overexpression of these proteins leads to enzymatic hyperactivity of the complex, which translates into aberrant repression of tumor suppressor genes in diverse cancers. Thus, targeting the inactivation of the PRC2 complex with chemical probes has emerged as a high-priority strategy to develop novel epigenetic cancer therapies. This idea has been supported by prior studies in which knockdown or knockout of EZH2 or EED impaired proliferation of MLL-AF9 cells, and by recent reports showing the utility of disabling PRC2 complex activity for the treatment of PCR2-dependent human cancers. Despite the importance of PcG proteins in cancer biology, the function of individual PcG members is still poorly understood. We are only beginning to understand now how the PcG proteins actually regulate their target genes. Discovering novel research tools useful to elucidate the specific role of these basic epigenetic regulators in neoplastic development is, therefore, an area of great interest. This proposal attempts to address this need by developing, for the first time, potent and proteolytically stable peptidomimetic and small-molecule inhibitors of the PcG proteins EED and SUZ12, two key components of the PRC2 complex. We have hypothesized that selective inhibition of the EED or SUZ12/repressive trimethyl-lysine association will abolish the PRC2 catalytic activity, and consequently, its biological functions. Hence, these chemical ligands could be useful not only to study the particular role of this protein in different cellular processes but also to decipher the role of PR2 target genes in cancer biology.

描述（由申请人提供）：Polycomb组蛋白（PCG）是转录阻遏物，它们结合编码蛋白质的启动子，编码蛋白质在许多细胞谱系中具有关键作用的蛋白质。这些蛋白质通过沉默不适当的表达并保持染色质抑制状态来介导其功能。已知PCG蛋白会形成两种通用类型的大型多聚体复合物，即PRC1和PRC2。 PRC2参与了基因抑制的开始，它具有内在的组蛋白甲基转移酶活性，对组蛋白H3的赖氨酸27（H3K27）的特异性（H3K27）具有特异性，而PRC1对于影响转录抑制很重要。大量文献将PRC2成分EZH2，EED和SUZ12连接到肿瘤起源，预后不良和肿瘤增殖。这些蛋白质的过表达导致复合物的酶促多动，这转化为对各种癌症中肿瘤抑制基因的异常抑制。因此，将PRC2复合物用化学探针的灭活靶向已成为开发新型表观遗传癌疗法的高优先级策略。先前的研究支持了这一想法，其中敲低或敲除ezh2或EED损害了MLL-AF9细胞的增殖，并且最近的报道显示了禁用PRC2复杂活性以治疗PCR2依赖性人类癌症的实用性。尽管PCG蛋白在癌症生物学中的重要性很重要，但单个PCG成员的功能仍然知之甚少。现在，我们才开始了解PCG蛋白如何实际调节其靶基因。因此，发现新的研究工具可用于阐明这些基本表观遗传调节剂在肿瘤发育中的特定作用，这是一个引人注目的领域。该提议试图通过首次开发有效和蛋白水解稳定的肽类似和小分子抑制剂EED和SUZ12（PRC2复合物的两个关键成分）来解决这种需求。我们假设选择性抑制EED或SUZ12/抑制性三甲基赖氨酸关联将废除PRC2催化活性，从而消除其生物学功能。因此，这些化学配体不仅可以研究该蛋白在不同的细胞过程中的特殊作用，而且还可以破译PR2靶基因在癌症生物学中的作用。