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

• 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
• 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

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，其结合编码在许多细胞谱系中的细胞命运决定中具有关键作用的蛋白质的基因的启动子。这些蛋白质通过沉默不适当的表达和维持染色质抑制状态来介导其功能。已知PcG蛋白形成两种一般类型的大的多聚体复合物，PRC 1和PRC 2。PRC 2参与基因阻遏的启动，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（H3 K27）具有特异性，而PRC 1对影响转录阻遏是重要的。大量文献将PRC 2组分EZH 2、EED和SUZ 12与肿瘤发生、不良预后和肿瘤增殖联系起来。这些蛋白质的过度表达导致复合物的酶活性过高，这转化为不同癌症中肿瘤抑制基因的异常抑制。因此，用化学探针靶向PRC 2复合物的失活已经成为开发新型表观遗传癌症疗法的高优先级策略。这一想法得到了先前研究的支持，其中EZH 2或EED的敲低或敲除损害了MLL-AF 9细胞的增殖，并且最近的报道显示了使PRC 2复合物活性失能用于治疗PCR 2依赖性人类癌症的效用。尽管PcG蛋白在癌症生物学中的重要性，但PcG成员的功能仍然知之甚少。我们现在才开始了解PcG蛋白实际上是如何调节其靶基因的。因此，发现新的研究工具有助于阐明这些基本的表观遗传调节因子在肿瘤发展中的具体作用，是一个非常感兴趣的领域。该提案试图通过首次开发PcG蛋白EED和SUZ 12（PRC 2复合物的两个关键组分）的有效且蛋白水解稳定的肽模拟物和小分子抑制剂来解决这一需求。我们假设选择性抑制EED或SUZ 12/抑制性三甲基赖氨酸结合将消除PRC 2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用于研究这种蛋白在不同细胞过程中的特定作用，而且可用于破译PR 2靶基因在癌症生物学中的作用。