Screening for inhibitors of NSD3 as a treatment for lung cancer

筛选 NSD3 抑制剂治疗肺癌

基本信息

批准号：
10562214
负责人：
Jolanta Grembecka
金额：
$ 52.95万
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：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10562214
关键词：
Affinity Animal Model Binding Biochemical Biological Assay Biology Biophysics Bladder Breast Cancer Model Cancer Patient Cancer cell line Cell Line Cells Chemicals Clinical Clinical Research Clinical Trials Complex Development Dose EZH2 gene Family member Fluorescein Fluorescence Polarization Follicular Lymphoma Future Genetic study Genomics Goals Head and neck structure Histones In Vitro Label Libraries Link Lung Lysine Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Malignant neoplasm of urinary bladder Mammalian Cell Measures Menin Michigan Non-Small-Cell Lung Carcinoma Nuclear Family Nuclear Receptors Nuclear Structure Oncogenes Oncogenic Outcome Pancreas Patients Play Protein Family Proteins Reporting Role SET Domain Series Squamous Cell Lung Carcinoma Structure-Activity Relationship Tertiary Protein Structure Testing Therapeutic Transcriptional Activation Universities analog biophysical techniques cancer cell drug discovery druggable target experimental study high throughput screening histone methyltransferase human disease in vivo inhibitor lung cancer cell malignant breast neoplasm member meter novel anticancer drug novel therapeutics osteosarcoma overexpression receptor binding sarcoma screening small molecule small molecule inhibitor small molecule libraries tumorigenesis

Affinity Animal Model Binding Biochemical Biological Assay Biology Biophysics Bladder Breast Cancer Model Cancer Patient Cancer cell line Cell Line Cells Chemicals Clinical Clinical Research Clinical Trials Complex Development Dose EZH2 gene Family member Fluorescein Fluorescence Polarization Follicular Lymphoma Future Genetic study Genomics Goals Head and neck structure Histones In Vitro Label Libraries Link Lung Lysine Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Malignant neoplasm of urinary bladder Mammalian Cell Measures Menin Michigan Non-Small-Cell Lung Carcinoma Nuclear Family Nuclear Receptors Nuclear Structure Oncogenes Oncogenic Outcome Pancreas Patients Play Protein Family Proteins Reporting Role SET Domain Series Squamous Cell Lung Carcinoma Structure-Activity Relationship Tertiary Protein Structure Testing Therapeutic Transcriptional Activation Universities analog biophysical techniques cancer cell drug discovery druggable target experimental study high throughput screening histone methyltransferase human disease in vivo inhibitor lung cancer cell malignant breast neoplasm member meter novel anticancer drug novel therapeutics osteosarcoma overexpression receptor binding sarcoma screening small molecule small molecule inhibitor small molecule libraries tumorigenesis

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项目摘要

Abstract The nuclear receptor binding SET domain protein 3 (NSD3) belongs to the family of NSD histone methyltransferases, which are responsible for mono- and di-methylation of lysine 36 on histone 3 (H3K36me1/2). Increasing number of studies link NSD3 to various cancers, including lung, breast, pancreatic and bladder cancers. Resent study implicates NSD3 as an oncogene in aggressive lung squamous cell carcinoma (LUSC), which represents a sub-type of non-small cell ling cancer with very poor clinical outcome. NSD3 in amplified and/or overexpressed in LUSC, and its role as an oncogene in this sub-type of lung cancer has been well validated using genetic studies, both in vitro and in vivo. Furthermore, the catalytic activity of NSD3 plays a critical role in LUSC oncogenesis, supporting that small molecule inhibitors of the catalytic SET domain of NSD3 could represent new therapeutics for lung cancer patients. However, NSD3 inhibitors have not been reported to date, but are highly desired as new potential therapeutics for patients with LUSC and other cancers with NSD3 amplifications. In this project we propose to develop NSD3 inhibitors by performing high throughput screening (HTS) at CCG, University of Michigan. The HTS will focus on identification of small molecule inhibitors of the catalytic SET domain of NSD3. To date, we developed and validated a fluorescence polarization (FP) assay that will be used as a primary screening assay for HTS to identify NSD3 inhibitors. Small molecules identified by HTS will be validated for binding to NSD3 and for inhibition of its catalytic activity using a series of biochemical and biophysical experiments, including NMR, ITC, and histone methyltransferase assays. Activity of the most potent compounds will be characterized in cell-based studies to assess inhibition of NSD3 in mammalian cells and understand their mechanism of action. Selected NSD3 inhibitors will be tested in a panel of lung cancer cell lines with NSD3 amplifications and/or overexpression for their activity, selectivity, and mechanism of action. In summary, we expect to identify highly valuable chemical probes selectively targeting catalytic SET domain of NSD3, which will be suitable for mechanistic studies in cancer cells. This project will pave the way towards development of more potent NSD3 inhibitors that will be appropriate for in vivo studies in lung cancer models and for future therapeutic implications.

抽象的核受体结合集合域蛋白3（NSD3）属于NSD组蛋白家族甲基转移酶，负责组蛋白3（H3K36ME1/2）上赖氨酸36的单甲基化和二甲基化。越来越多的研究将NSD3与各种癌症联系起来，包括肺，乳房，胰腺和膀胱癌症。怨恨研究将NSD3视为侵袭性肺鳞状细胞癌（LUSC）中的癌基因，这代表了非小细胞笼癌的子类型，其临床结局非常差。 NSD3放大和/或在LUSC中过表达，及其作为癌基因在这种肺癌亚类型中的作用一直很好使用体外和体内的遗传研究验证。此外，NSD3的催化活性播放A 在LUSC肿瘤发生中的关键作用，支持NSD3的催化集域的小分子抑制剂可以代表肺癌患者的新疗法。但是，尚未报告NSD3抑制剂日期，但高度期望作为LUSC患者和其他NSD3癌症患者的新潜在疗法放大。在这个项目中，我们建议通过进行高通量筛选来开发NSD3抑制剂（HTS）位于密歇根大学CCG。 HTS将专注于鉴定小分子抑制剂 NSD3的催化集域。迄今为止，我们开发并验证了荧光极化（FP）测定法将用作HTS鉴定NSD3抑制剂的主要筛选测定法。 HTS鉴定的小分子将通过一系列生化和生物物理实验，包括NMR，ITC和组蛋白甲基转移酶测定。最有力的活动化合物将在基于细胞的研究中进行表征，以评估哺乳动物细胞中NSD3的抑制了解他们的行动机制。选定的NSD3抑制剂将在一组肺癌细胞系中进行测试具有NSD3扩增和/或过表达的活动，选择性和作用机理。在总而言之，我们期望确定高价值的化学探针选择性地靶向催化固定域 NSD3，适用于癌细胞中的机械研究。这个项目将为通往开发更有效的NSD3抑制剂，这些抑制剂适用于肺癌模型中的体内研究以及未来的治疗意义。