Targeting crotonyl-lysine chromatin readers to disrupt pathogenic gene expression in leukemia

靶向巴豆酰赖氨酸染色质读取器破坏白血病致病基因表达

基本信息

批准号：
10247784
负责人：
Michael A Erb
金额：
$ 48.38万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
2018-09-07 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10247784
关键词：
Acetylation Acute leukemia Affinity Animal Model Appointment Binding Binding Sites Biochemical Biological Biological Assay Biological Models Biology Biomedical Research Bromodomain California Cell Proliferation Cell Survival Cell model Chemicals Chemistry Chromatin Chromatin Structure Collaborations Computational Biology Data Data Set Development Disease Doctor of Philosophy Drug Design Drug Industry ENL Protein Euchromatin Faculty Feedback Fostering Funding Fusion Oncogene Proteins Gene Expression Genes Genetic Genetic Transcription Genome Human In Vitro Infant Leukemia Infrastructure Institutes Institution Interdisciplinary Study Leukemic Cell Lysine Malignant Neoplasms Mediating Medical Medicine Mentorship Modeling Molecular Target Nature Oncogenic Outcome Output PHD Finger Pathogenesis Pathogenicity Pathway interactions Pharmaceutical Chemistry Positioning Attribute Productivity Proteins Publishing Reader Reporting Research Research Activity Research Institute Research Personnel Resistance Role Signal Transduction Structure Survival Rate Technical Expertise Testing Therapeutic Time Training Transcription Coactivator Transcriptional Regulation Validation Work base cancer cell career drug discovery experience experimental study genetic approach genomic data histone acetyltransferase histone modification in vivo inhibitor/antagonist innovation insight instrumentation leukemia novel open innovation pre-clinical programs promoter protein degradation protein function response screening small molecule small molecule inhibitor success therapeutic target tool transcription factor translational impact

项目摘要

PROJECT SUMMARY/ABSTRACT To support the cellular demands of unchecked proliferation and to maintain a malignant cell state through successive rounds of cellular division, cancer cells depend on lineage-specific, dysregulated gene expression programs. Thus, the chromatin regulators that underlie chromatin-dependent transcription control have been considered attractive targets to disrupt or diminish pathogenic transcriptional signaling. Previously, I led a research effort that established ENL, a transcriptional co-activator and chromatin reader protein, as a critical requirement for the survival of acute leukemia in cellular and animal model systems. Notably, its YEATS domain, a crotonyl-lysine-binding chromatin reader domain that anchors ENL at the promoters of transcriptionally active genes, is required for the pro-proliferative effects of ENL in leukemia. Moreover, preliminary data suggests that KAT6A, a histone acetyltransferase and crotonyl-lysine chromatin reader protein, is also required for acute leukemia pathogenesis. Here, I propose to further consider crotonyl-lysine reader proteins as potential therapeutic opportunities in acute leukemia with the following three specific aims. In the first aim, I will determine the cellular pathways and co-factors regulating response and resistance to loss of ENL in acute leukemia. Genetic experiments proposed within this aim will determine the cellular pathways and co-factors regulating ENL target biology to understand its mechanism of action in promoting leukemia cell proliferation and survival. In the second aim, I will test the hypothesis that the ENL YEATS domain can be disrupted by small-molecule inhibitors, which will serve both as chemical probes of ENL protein function and as starting points for translational development of ENL-targeted leukemia therapy. I will apply high-throughput chemical screens, structure-based drug design, and iterative medicinal chemistry to discover and optimize first-in-class ENL YEATS inhibitors. In the third aim, I will assess the role of crotonyl-lysine recognition by KAT6A in leukemia pathogenesis; I will use genetic approaches and targeted protein degradation to determine whether crotonyl-lysine recognition by the double PHD finger domain (DPF) of KAT6A is required for acute leukemia survival. Each proposed aim operates within early-stage drug discovery efforts (i.e. target validation and chemical tool discovery) and if successful, will provide biological insights and chemical tools that will enable timely translational development of novel, molecularly-targeted cancer medicines. In keeping with the model of open-innovation in academic drug discovery, all chemical probes, biological tools, and genomic datasets derived from this work will be made publicly and freely available, without restriction on use, so to broaden and accelerate the impact of this work.

项目概要/摘要支持不受抑制的增殖的细胞需求并通过以下方式维持恶性细胞状态在连续几轮的细胞分裂中，癌细胞依赖于谱系特异性、失调的基因表达程序。因此，染色质依赖性转录控制的染色质调节因子已被被认为是破坏或减少致病转录信号的有吸引力的目标。此前，我领导过一个研究工作将 ENL（一种转录共激活因子和染色质读取蛋白）确立为关键的急性白血病在细胞和动物模型系统中存活的要求。值得注意的是，它的 YEATS 域，巴豆酰赖氨酸结合染色质阅读器结构域，将 ENL 锚定在转录活性的启动子上基因，是 ENL 在白血病中发挥促增殖作用所必需的。此外，初步数据表明 KAT6A 是一种组蛋白乙酰转移酶和巴豆酰赖氨酸染色质读取蛋白，也是急性白血病发病机制。在这里，我建议进一步考虑巴豆酰赖氨酸阅读蛋白作为潜在的急性白血病的治疗机会具有以下三个具体目标。在第一个目标中，我将确定调节急性白血病中 ENL 丢失的反应和抵抗力的细胞途径和辅助因子。在此目标中提出的基因实验将确定调节 ENL 的细胞途径和辅助因子目标生物学以了解其促进白血病细胞增殖和存活的作用机制。在第二个目标，我将测试 ENL YEATS 结构域可以被小分子抑制剂破坏的假设，它将既作为 ENL 蛋白功能的化学探针，又作为翻译的起点 ENL靶向白血病治疗的发展。我将应用基于结构的高通量化学筛选药物设计和迭代药物化学，以发现和优化一流的 ENL YEATS 抑制剂。在第三个目标，我将评估 KAT6A 识别巴豆酰赖氨酸在白血病发病机制中的作用；我会用遗传方法和靶向蛋白质降解以确定巴豆酰赖氨酸是否被 KAT6A 的双 PHD 指结构域 (DPF) 是急性白血病存活所必需的。每个提议的目标都在运作在早期药物发现工作（即目标验证和化学工具发现）中，如果成功，将提供生物学见解和化学工具，使新的、分子靶向癌症药物。符合学术药物开放创新模式发现，所有源自这项工作的化学探针、生物工具和基因组数据集都将被制作公开且免费提供，不受使用限制，从而扩大和加速这项工作的影响。