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

• 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
• 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

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/项目总结