Targeting epigenetic reader GAS41

靶向表观遗传阅读器 GAS41

基本信息

批准号：
10368999
负责人：
Tomasz Cierpicki
金额：
$ 49.72万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10368999
关键词：
Affinity Animal Model Antineoplastic Agents Astrocytoma Bees Binding Biochemical Biological Assay Biology Biophysics Cancer Biology Cancer Cell Growth Cancer cell line Cells Chemicals Chromatin Clinical Trials Colon Development Dimerization Dose Drug Targeting Epigenetic Process Fluorescence Polarization Foundations Future GAS41 gene Genetic Transcription Genomics Glioblastoma Goals Histone Acetylation Histone H3 Histones Human Investigational Therapies Length Libraries Ligands Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Measures Methods Michigan Non-Small-Cell Lung Carcinoma Oncogenes Oncogenic Outcome Play Post-Translational Protein Processing Proteins Reader Regulation Reporting Research Personnel Role Series Structure Structure-Activity Relationship Testing Universities X-Ray Crystallography analog base cancer cell cytotoxic design dimer drug discovery experience experimental study high throughput screening histone modification in vivo inhibitor knock-down lung cancer cell novel novel therapeutic intervention protein protein interaction screening small molecule small molecule inhibitor small molecule libraries structural biology tumor tumorigenesis

项目摘要

Abstract Post-translational modifications on histone proteins play an essential role in regulating chromatin transcription in human cancers. Histone acetylation is associated with active gene transcription and plays a crucial role in tumorigenesis. Indeed, small molecules targeting proteins involved in regulation of histone modifications are being explored as a very promising anti-cancer agents, with a number of compounds currently in clinical trials (e.g. BRD4 inhibitors). Recently, the YEATS domains have been discovered as novel acetyl-histone reader domains. GAS41 was originally found to be amplified in 23% glioblastomas and 80% astrocytoma. Emerging studies strongly implicate GAS41 as an oncogene in Non-Small Cell Lung Cancer (NSCLC). GAS41 is frequently amplified in NSCLC and knockdown of GAS41 or disruption of the interaction with acetylated histones suppresses lung cancer cell growth. We have recently found that GAS41 is a reader of di-acetylated H3 histone. Full-length GAS41 is dimeric in cells and binds di-acetylated H3 with high affinity. Based on this finding we developed suites of biochemical assays suitable for characterization of GAS41 protein-protein interactions and identification of small molecule inhibitors. In this proposal we plan to develop small molecule inhibitors of GAS41 using high throughput screening (HTS) in CCG at the University of Michigan. Small molecule inhibitors of GAS41 will be validated and characterized in a series of biochemical and biophysical experiments. Activity of the most potent compounds will be characterized in cell-based assays to assess the disruption of GAS41 interactions with chromatin and understand mechanism of action. Selected GAS41 inhibitors will be also profiled in a panel of lung cancer cell lines. In summary, we expect to identify highly valuable chemical probe compounds targeting GAS41 protein-protein interactions suitable for mechanistic studies and pave the way towards development of potent in vivo active GAS41 inhibitors.

抽象的组蛋白的翻译后修饰在调节染色质转录中发挥重要作用在人类癌症中。组蛋白乙酰化与活跃的基因转录相关，并在肿瘤发生。事实上，针对参与组蛋白修饰调节的蛋白质的小分子是正在被探索作为一种非常有前途的抗癌药物，目前有许多化合物正在进行临床试验（例如 BRD4 抑制剂）。最近，YEATS 结构域被发现是一种新型乙酰组蛋白阅读器域。 GAS41 最初被发现在 23% 的胶质母细胞瘤和 80% 的星形细胞瘤中扩增。新兴研究强烈表明 GAS41 是非小细胞肺癌 (NSCLC) 的癌基因。 GAS41 是在 NSCLC 中频繁扩增，并敲低 GAS41 或破坏与乙酰化的相互作用组蛋白抑制肺癌细胞的生长。我们最近发现 GAS41 是二乙酰化 H3 组蛋白的阅读器。全长 GAS41 是二聚体细胞并以高亲和力结合二乙酰化 H3。基于这一发现，我们开发了生化套件适用于 GAS41 蛋白质-蛋白质相互作用表征和小分子鉴定的测定抑制剂。在本提案中，我们计划利用高通量开发 GAS41 的小分子抑制剂密歇根大学 CCG 筛查 (HTS)。 GAS41的小分子抑制剂将得到验证并通过一系列生物化学和生物物理实验进行表征。最有力的活动化合物将在基于细胞的测定中进行表征，以评估 GAS41 与染色质并了解作用机制。选定的 GAS41 抑制剂也将在一组中进行分析肺癌细胞系。总之，我们期望识别出非常有价值的化学探针化合物，目标是 GAS41蛋白质-蛋白质相互作用适合机制研究并为开发铺平道路有效的体内活性 GAS41 抑制剂。