Targeting MLL3 histone methyltransferase

靶向 MLL3 组蛋白甲基转移酶

• 批准号: 9241886
• 负责人: Yali Dou
• 金额: $ 35.46万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241886
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Adult; Affect; Animal Model; Biochemical; Biological; Biological Assay; Biological Process; Biology; Biophysics; Cancer Patient; Cell model; Cells; Cellular Assay; Chemicals; Chromatin; Colorectal; Common Core; Complex; DNA; DNA Modification Methylases; Data; Development; Disease; Disease Progression; EZH2 gene; Enhancers; Enzymes; Epigenetic Process; Event; Family; Family member; Gene Activation; Gene Expression; Gene Targeting; Generations; Genes; Genetic study; Goals; Growth; Histone Deacetylase; Histone H3; Histone-Lysine N-Methyltransferase; Human; Lead; Link; Lung; Lysine; MLL gene; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of lung; Mammals; Mediating; Methylation; Methyltransferase; Mixed-Lineage Leukemia; Molecular; Molecular Probes; Mutation; Myeloid-Lymphoid Leukemia Protein; Neonatal Leukemia; Obesity; Pathologic; Pathway interactions; Pharmacology; Phenocopy; Physiological; Play; Prevalence; Proteins; Reader; Recruitment Activity; Regulation; Regulatory Element; Reproducibility; Research; Role; Series; Specificity; Stomach; Structure; Transcriptional Activation; Transcriptional Regulation; Treatment Efficacy; Work; base; cell growth; chromatin modification; clinical efficacy; cofactor; drug development; enzyme activity; epigenetic regulation; genome-wide analysis; high throughput screening; histone methylation; histone methyltransferase; histone modification; human disease; infancy; inhibitor/antagonist; insight; interest; leukemia/lymphoma; loss of function mutation; novel; novel therapeutic intervention; prevent; promoter; public health relevance; screening; small molecule inhibitor; small molecule libraries; tool; transcriptome; tumor progression

 DESCRIPTION (provided by applicant): Accumulating evidence suggests that epigenetic pathways play an integral role in the sequential progression of cancer. It is shown that many epigenetic enzymes are targeted for mutation and deregulation in cancer patients. Inhibitors of several key epigenetic enzymes including DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) have proven to be instrumental for both basic understanding of the function of the respective activity of the enzymes and applications in cancer epigenetic therapy. However, efforts in development of inhibitors for histone methyltransferase inhibitors are still at its infancy. The overall goal of this project is to develop potent and selective inhibitors for histone methyltransferase MLL3. Furthermore, we will also develop a series of facile, sensitive and reproducible high-throughput screening assays ready to identify potent, selective inhibitors for other histone methyltransferase (HMT) activity. There are at least six MLL family HMTs. MLL proteins use the SAM cofactor to methylate histone H3 lysine residue 4 and work in concert with other histone modification enzymes to provide a mechanistic link between chromatin alteration and gene activation; and regulate different biological processes through recruitment of various H3K4 'reader' proteins. MLL mutations and dys-regulation have been correlated with several human diseases including various cancers (leukemia, lymphoma, colorectal, gastric and lung), obesity and human intelligent deficiency. Because of the interesting biology that is mediated by MLLs and their involvement to human diseases, it is of interest to develop novel small molecule inhibitors that might serve as biological probes as well as lead molecules for drug development. For this application, we will focus our screening efforts on the MLL3 protein, although the assay should be generally applicable to other MLL family HMTs. The specific aims of the proposal are to (1) Develop a high-throughput screen and counter screen for MLL3 inhibitors, (2) Develop an secondary assay to quantify the potency and to biochemically characterize candidate hit compounds identified in high-throughput screens, and (3) Assess compound on-target specificity in cellular assays and genome-wide studies. We expect these studies to define biochemical and cell based assays to screen large libraries of small molecules to identify potent and selective inhibitors of MLL3 histone methyltransferase, and to obtain some pan-MLL inhibitors that target global H3K4 methylation. We anticipate that these studies will result in the identification of potent and selective first-generation MLL3 inhibitors for further development as chemical probes.

 描述（由申请人提供）：越来越多的证据表明表观遗传途径在癌症的连续进展中发挥着不可或缺的作用。研究表明，许多表观遗传酶是癌症患者突变和失调的靶点。包括 DNA 甲基转移酶 (DNMT) 和组蛋白脱乙酰酶 (HDAC) 在内的几种关键表观遗传酶的抑制剂已被证明有助于基本了解这些酶各自活性的功能以及在癌症表观遗传治疗中的应用。然而，组蛋白甲基转移酶抑制剂的开发仍处于起步阶段。 它的婴儿期。该项目的总体目标是开发组蛋白甲基转移酶 MLL3 的有效且选择性抑制剂。此外，我们还将开发一系列简便、灵敏和可重复的高通量筛选方法，以鉴定其他组蛋白甲基转移酶（HMT）活性的有效、选择性抑制剂。至少有六个 MLL 家族 HMT。 MLL 蛋白使用 SAM 辅因子将组蛋白 H3 赖氨酸残基 4 甲基化，并与其他组蛋白修饰酶协同工作，在染色质改变和基因激活之间提供机制联系；并通过招募各种 H3K4“阅读器”蛋白来调节不同的生物过程。 MLL 突变和失调与多种人类疾病相关，包括各种癌症（白血病、淋巴瘤、结直肠癌、胃癌和肺癌）、肥胖和人类智力缺陷。由于 MLL 介导的有趣生物学及其与人类疾病的关系，人们对开发新型小分子抑制剂感兴趣，这些抑制剂可以作为生物探针以及药物开发的先导分子。对于此应用，我们将把筛选工作集中在 MLL3 蛋白上，尽管该测定应该普遍适用于其他 MLL 家族 HMT。该提案的具体目标是 (1) 开发 MLL3 抑制剂的高通量筛选和反筛选，(2) 开发二次测定法来量化效力，并对高通量筛选中鉴定的候选命中化合物进行生化表征，以及 (3) 评估细胞测定和全基因组研究中化合物的靶向特异性。我们期望这些研究能够定义生化和基于细胞的测定法，以筛选大型小分子文库，以确定 MLL3 组蛋白甲基转移酶的有效和选择性抑制剂，并获得一些针对全局 H3K4 甲基化的泛 MLL 抑制剂。我们预计这些研究将导致 鉴定有效且选择性的第一代 MLL3 抑制剂，以进一步开发为化学探针。