Identification and characterization of chemical probes for interrogation of the NEK family of kinases in cancer

用于研究癌症中 NEK 激酶家族的化学探针的鉴定和表征

基本信息

批准号：
10503430
负责人：
Matthew E. Burow
金额：
$ 63.61万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10503430
关键词：
3-Dimensional Active Sites Address Antineoplastic Agents Binding Biological Biological Assay Biological Process Biology Cell Cycle Cell Cycle Regulation Cell Line Cells Cellular biology Chemicals Communities DNA Damage DNA biosynthesis Data Development Diabetes Mellitus Disadvantaged Disease Disease Progression Drug Targeting Environment Etiology FDA approved Family Family member Foundations Free Will Funding Generations Genome Health Human Individual Inflammation Inflammatory Bowel Diseases Knock-out Knowledge Left Link Malignant Neoplasms Measures Medicine Mission Mitosis Modality Molecular Nature Neurons Oncology Output Pathologic Pathway interactions Pharmaceutical Chemistry Pharmaceutical Preparations Phosphotransferases Physiological Play Process Protein Family Protein Kinase Proteins Proteome RNA Splicing Reagent Reporter Research Research Personnel Resources Role Scientist Signal Pathway Signal Transduction System Therapeutic United States National Institutes of Health Validation Work base cancer therapy cell motility chronic inflammatory disease ciliopathy cilium biogenesis design drug development drug discovery drug quality druggable target holistic approach inhibitor insight knock-down lead optimization member migration new therapeutic target programs response scaffold small molecule success tool

项目摘要

ABSTRACT / PROJECT SUMMARY Kinases, a class of proteins with more than 500 members in the human proteome, are important regulators of biological processes in health and disease. Kinases have proven to be excellent drug targets with more than 70 FDA approved medicines that target kinases. Despite this success, most kinases are understudied, and details of their functions are poorly understood. The NEK family of 11 kinases (NEK1 through NEK11) is a particularly understudied set of kinases that play roles in key biological processes like the cell cycle, ciliogenesis, and the DNA damage response (DDR), all with relevance to cancer and human health. These kinases have emerging links to numerous cancers, diabetes, inflammatory bowel disease, ciliopathies, and ALS. In this project we will use an efficient kinase systems-based approach to create an enabling suite of chemical probes, assays, reagents, and molecular tools to identify NEK family members that have key roles in cancer. These high-quality compounds and reagents we generate, which we will freely share, will allow scientists to build a deep understanding of the physiological and pathological roles members of the NEK family play. In Aim 1 we will create potent and selective inhibitors of each NEK using iterative medicinal chemistry and state of the art in cell target engagement assays. In a complementary effort for this aim we will also create inducible NEK knockdown cell lines. In Aim 2, using compounds and the NEK knockdown lines, we will evaluate the role and importance of each NEK in a suite of NEK and oncology-relevant cell health and cell biology signaling assays, measuring effects on proliferation, migration, the cell-cycle, DNA replication, and ciliogenesis. In Aim 3 we will experimentally determine the substrates of each NEK, locate the NEKs in broader kinase-dependent signaling pathways, and develop genetically targetable kinase activity reporters for tracking NEK activity within the endogenous cellular environment. Output from this project will include potent and selective NEK inhibitors, NEK family-wide assays, details on the impact of NEK inhibition and knockdown on key cancer processes, molecular tools, and NEK substrate and pathway information. Successful completion will provide a framework and the resources needed to validate individual NEKs as high quality, druggable targets for the treatment of cancer.

摘要 /项目摘要激酶是人类蛋白质组中有500多名成员的一类蛋白质，是重要的调节剂健康和疾病的生物过程。事实证明，激酶是优秀的药物靶标，超过70个 FDA批准了针对激酶的药物。尽管取得了成功，但大多数激酶都被研究了，细节他们的功能知之甚少。 11个激酶的NEK家族（NEK1至NEK11）是一个特别是在关键生物学过程中起作用的一组激酶，例如细胞周期，纤毛生成和 DNA损伤反应（DDR）与癌症和人类健康有关。这些激酶有新兴链接到许多癌症，糖尿病，炎症性肠病，纤毛病和ALS的链接。在这个项目中，我们将使用有效的激酶系统方法来创建启示套件的化学探针套件，测定，试剂和分子工具，用于识别在癌症中具有关键作用的NEK家族成员。这些高质量我们生成的化合物和试剂（我们将自由分享）将使科学家能够建立一个深刻的了解NEK家族发挥的生理和病理角色成员。在目标1中，我们将使用迭代药物化学和细胞中的艺术状态，创建每个NEK的有效和选择性抑制剂目标参与分析。在为此目标的互补工作中，我们还将创建可诱导的NEK敲低细胞系。在AIM 2中，使用化合物和NEK敲低线，我们将评估 NEK和与肿瘤相关的细胞健康和细胞生物学信号传导分析中的每个NEK，测量对增殖，迁移，细胞周期，DNA复制和纤毛发生的影响。在目标3中，我们将实验确定每个NEK的底物，将NEK定位在较宽的激酶依赖性信号中途径，并开发具有遗传靶向激酶活性报告基因以跟踪NEK活性内源性细胞环境。该项目的输出将包括有效和选择性的NEK抑制剂，NEK 家庭范围的测定，NEK抑制作用和敲低对关键癌症过程的细节，分子工具，NEK基材和途径信息。成功完成将提供一个框架和为了验证单个NEK是高质量的，可吸毒的靶标所需的资源。