Characterization of an understudied kinase, NEK5, in acquisition of a mesenchymaland migratory cell phenotype

一种正在研究的激酶 NEK5 在获取间充质细胞和迁移细胞表型中的表征

• 批准号: 10047560
• 负责人: Matthew E. Burow
• 金额: $ 16.68万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-08 至 2022-09-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10047560
• 关键词: Basic Science; Binding; Biological; Biological Assay; Biological Models; Biological Process; Biology; Breast Cancer Cell; Breast Cancer Model; Breast Cancer cell line; Cancer Biology; Cells; Cellular biology; Cessation of life; Chemicals; Clinic; Clinical; Communities; Data; Development; Disease; Disseminated Malignant Neoplasm; Distal; Drug Regulations; Drug Targeting; Drug resistance; Epithelial; Epithelium; FDA approved; Family; Family member; Follow-Up Studies; Foundations; Future; Gene Expression; Genome; Goals; Grant; Health; Human; Lead; Libraries; Link; Malignant Neoplasms; Mesenchymal; Mitosis; Modeling; Morphology; Nature; Neoplasm Metastasis; Oncology; Output; Pathologic; Pathway interactions; Patients; Pharmaceutical Chemistry; Phenotype; Phosphotransferases; Play; Positioning Attribute; Primary Neoplasm; Process; Proteins; Publishing; Pyrimidine; Reagent; Regulation; Reporting; Research; Resources; Role; Signal Pathway; Signal Transduction; Site; Structure-Activity Relationship; System; Techniques; Testing; Therapeutic; Tissues; Translational Research; Tumor Biology; Ursidae Family; Validation; Work; Xenograft Model; analog; cancer cell; cancer clinical trial; cancer subtypes; cancer therapy; cell motility; cellular targeting; clinical candidate; drug development; drug discovery; effective therapy; epithelial to mesenchymal transition; experience; experimental study; genetic manipulation; genome resource; human disease; human model; in vivo; in vivo evaluation; inhibitor/antagonist; interest; kinase inhibitor; malignant breast neoplasm; member; migration; multidisciplinary; novel; novel anticancer drug; novel therapeutics; scaffold; small molecule; small molecule inhibitor; success; targeted treatment; tool; triple-negative invasive breast carcinoma; tumor progression; tumorigenesis

Project Summary /Abstract Metastasis, or the spread of cancer cells from a primary tumor to distal tissue sites, is responsible for 90% of cancer-related deaths. Metastasis is a step-by-step process, with the major steps being initiation, invasion, migration, seeding, and colonization. Certain kinase families have been extensively studied as regulators of cell motility/invasion and epithelial-mesenchymal transition (EMT). Our preliminary data revealed members of the NEver-in-mitosis-related Kinase family (NEK5, NEK1 and NEK9) involved in the progression to the EMT phenotype. Previous studies demonstrate NEK9 and NEK1 are upstream regulators of PLK expression, but NEK5 remains uncharacterized. The use of kinase inhibitors to dissect and validate targetable nodes within cancer signaling pathways has revolutionized oncology drug discovery. Among the most interesting understudied IDG kinases is NEK5, a kinase linked to the critical biological process of epithelial to mesenchymal transition (EMT). Our preliminary evidence demonstrates that NEK5 is involved in pathways of significant pathological importance in difficult to treat breast cancer subtypes. There is an immediate need for potent, selective, and cell active NEK5 inhibitors that can be used to define the roles of NEK5 in EMT and evaluate the therapeutic potential of NEK5 inhibitors in relevant models of human disease. Here we propose a medicinal chemistry approach to optimize a promising inhibitor scaffold that we have identified and that has been declared an IDG tool molecule. In Aim 1 we will synthesize new analogues of the IDG tool in order to optimize cellular activity and selectivity. We will optimize cellular potency using an IDG resource assay: the NEK5 nanoBRET in cell target engagement assay. We will optimize selectivity as judged by broad kinome profile of our best molecules. The deliverable from Aim 1 will be a potent, cell active, narrow spectrum NEK5 inhibitor. These results will pave the way for further work to optimize this NEK5 scaffold into compounds that can be tested in vivo and in the clinic. In Aim 2 we will focus on delineating the biological role for NEK5 using triple negative breast cancer cell lines and patient derived xenograft model systems. To accomplish our goals, we have taken advantage of IDG published resources, and assembled a collaborative, multidisciplinary team with experience in kinase inhibitor optimization, cell biology, and tumor biology. Successful completion of this project will deliver a high quality NEK5 inhibitor, details on the roles NEK5 plays in the EMT, metastasis and tumorigenesis, and preliminary validation of NEK5 as a promising oncology drug discovery target for aggressive, hard to treat breast cancer subtypes. Results from experiments here may pave the way to new drugs for cancer treatment that target the understudied kinase NEK5. Free distribution of the NEK5 tool molecules will allow the community to determine other roles this IDG understudied kinase plays in signaling cascades in health and disease.

项目总结/摘要 转移，或癌细胞从原发性肿瘤扩散到远端组织部位，是导致90%的肿瘤转移的原因。 与癌症有关的死亡转移是一个逐步的过程，主要步骤是启动，侵袭， 迁徙播种和殖民某些激酶家族已被广泛研究作为细胞增殖的调节因子。 运动/侵袭和上皮-间质转化（EMT）。我们的初步数据显示， NEVER-有丝分裂相关激酶家族（NEK 5、NEK 1和NEK 9）参与EMT的进展 表型以往的研究表明，NEK 9和NEK 1是PLK表达的上游调节因子，但 NEK 5仍然没有特征。使用激酶抑制剂来解剖和验证 癌症信号通路已经彻底改变了肿瘤药物的发现。最有趣的替补演员之一 IDG激酶是NEK 5，一种与上皮细胞向间充质细胞转化的关键生物过程相关的激酶 （EMT）。我们的初步证据表明，NEK 5参与了重要的病理学途径， 在难以治疗的乳腺癌亚型中的重要性。目前迫切需要一种有效的、有选择性的、细胞 活性NEK 5抑制剂，可用于确定NEK 5在EMT中的作用并评估治疗潜力 NEK 5抑制剂在人类疾病相关模型中的应用。在这里，我们提出了一种药物化学方法， 优化一个有前途的抑制剂支架，我们已经确定，并已宣布IDG工具分子。 在目标1中，我们将合成IDG工具的新类似物，以优化细胞活性和选择性。 我们将使用IDG资源分析优化细胞效能：细胞靶向接合中的NEK 5 nanoBRET 比色法我们将根据我们最好分子的广泛激酶组特征来优化选择性。可交付成果来自 Aim 1将是一种有效的、细胞活性的、窄谱的NEK 5抑制剂。这些结果将为进一步的研究铺平道路。 我们致力于将NEK 5支架优化为可以在体内和临床上进行测试的化合物。在目标2中， 专注于使用三阴性乳腺癌细胞系和患者来源的细胞系来描绘NEK 5的生物学作用。 异种移植模型系统。为了实现我们的目标，我们充分利用了IDG发布的资源， 组建了一个具有激酶抑制剂优化，细胞生物学， 和肿瘤生物学该项目的成功完成将提供高质量的NEK 5抑制剂，详细信息请参阅 NEK 5在EMT、转移和肿瘤发生中的作用，以及NEK 5作为一种有前途的 肿瘤学药物发现靶点为侵袭性的，难以治疗的乳腺癌亚型。的实验的结果 这可能为靶向研究不足的激酶NEK 5的癌症治疗新药铺平道路。免费 NEK 5工具分子的分发将使社区能够确定IDG未充分研究的其他作用 激酶在健康和疾病的信号级联中起作用。