Elucidating the Understudied Kinase PNCK as a Prospective Drug Target in Renal Cell Carcinoma

阐明正在研究的激酶 PNCK 作为肾细胞癌的潜在药物靶点

• 批准号: 10667043
• 负责人: Stephan C Schurer
• 金额: $ 15.94万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10667043
• 关键词: Advanced Development; Apoptosis; Binding; Biological; Biological Assay; Biological Process; Biology; Biomedical Research; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calmodulin; Cancer Model; Cell Cycle Arrest; Cell Line; Cell Proliferation; Cells; Chemicals; Clinical; Clinical Research; Complement; Computer Models; DNA Damage; Darkness; Data; Data Analyses; Dedications; Development; Disease; Disease Resistance; Drug Combinations; Drug Targeting; Family; Future; Genetic Transcription; Genome; Goals; Growth; Histopathologic Grade; Human; Human Genome; Immunotherapy; Incidence; Knowledge; Knowledge Portal; Lead; Link; Literature; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular; Normal tissue morphology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphotransferases; Play; Pregnancy; Pregnancy Proteins; Prognosis; Program Development; Proliferating; Proteins; Proteomics; Receptor Protein-Tyrosine Kinases; Renal Cell Carcinoma; Renal carcinoma; Resistance development; Resources; Role; Signal Transduction; System; The Cancer Genome Atlas; Therapeutic; Tumor Tissue; Tyrosine Kinase Inhibitor; Work; analog; angiogenesis; anticancer research; antitumor effect; cell growth; drug development; drug discovery; effective therapy; improved; improved outcome; inhibitor; innovation; insight; kinase inhibitor; knock-down; lead optimization; multiple omics; new therapeutic target; novel; overexpression; programs; prospective; protein structure; response; small molecule; small molecule inhibitor; therapeutic development; transcriptome sequencing; transcriptomics; tumor; tumor progression; tumorigenesis

PROJECT SUMMARY The human kinome is one of the most established family of druggable proteins. Yet out of more than 600 kinases only a fraction is currently the focus of clinical studies and chemical probe development, and many kinases remain understudied. Kinase inhibitors play an important role in the treatment of human cancers, such as advanced renal cell carcinoma (RCC), a malignancy whose incidence is increasing and carries a poor prognosis. While RCC clinical outcomes are improving with tyrosine kinase inhibitors and immunotherapies, the majority of patients ultimately succumb to progressive, resistant disease. Our long-term goal is to find cures for advanced RCC by identifying and validating novel RCC kinase targets for drug development. PNCK is an understudied kinase. Analyzing the Illuminating the Druggable Genome (IDG) Knowledge Portal Pharos along with other resources revealed that PNCK is the most differentially overexpressed kinase in RCC patients and is associated with worse disease specific survival. In our preliminary studies PNCK overexpression led to significant increase in RCC cell growth and proliferation, while PNCK inhibition exerted direct antitumor effects, by inhibition of cell growth, induction of RCC cell cycle arrest and apoptosis, as well as indirect effects, by regulating expression of angiogenesis and DNA damage response pathways. These findings highlight the clinical and biological relevance of PNCK in RCC. The objective of this proposal is to generate and then integrate systems level signatures of PNCK in RCC with target-based kinase profiling of PNCK small molecule inhibitors to inform future chemical probe and drug lead optimization programs via two Specific Aims. Aim 1 will generate transcriptomics and active kinome signatures from PNCK overexpression and knockdown cell lines and identify PNCK-driven pathways and signaling networks by multi-omics analysis. Aim 2 will optimize and then characterize our current PNCK inhibitors using computational models and NanoBRET target engagement followed by kinase profiling to assess selectivity and off targets. Combined, the systems level signatures of PNCK in RCC and target-based kinase profiles of the best compounds will further elucidate the biology and therapeutic potential of PNCK in RCC and inform subsequent chemical probe and drug lead optimization projects. Our team combines complementary expertise in computational systems pharmacology / drug discovery (Schürer), translational kidney cancer research (Merchan), and multi-omics (including chemical proteomics MIB/MS) functional characterization of the cancer kinome (Johnson) to successfully complete the proposed project Aims.

项目概要 人类激酶组是最成熟的可药物蛋白家族之一。然而，在 600 多种激酶中 目前只有一小部分是临床研究和化学探针开发的重点，许多激酶 仍处于研究之中。激酶抑制剂在人类癌症的治疗中发挥着重要作用，例如 晚期肾细胞癌（RCC）是一种发病率不断增加且预后不良的恶性肿瘤。 尽管酪氨酸激酶抑制剂和免疫疗法正在改善肾细胞癌的临床结果，但大多数 患者最终死于进行性、耐药性的疾病。我们的长期目标是找到先进的治疗方法 通过识别和验证用于药物开发的新型 RCC 激酶靶标来实现 RCC。 PNCK 是一种尚未被研究的激酶。分析照亮可药物基因组 (IDG) 知识门户 Pharos 和其他资源揭示了 PNCK 是 RCC 中差异最大的过表达激酶 患者，并与较差的疾病特异性生存相关。在我们的初步研究中，PNCK 过度表达 导致 RCC 细胞生长和增殖显着增加，而 PNCK 抑制则发挥直接抗肿瘤作用 通过抑制细胞生长、诱导肾细胞癌细胞周期停滞和细胞凋亡以及间接影响， 通过调节血管生成和 DNA 损伤反应途径的表达。这些发现凸显了 PNCK 在 RCC 中的临床和生物学相关性。该提案的目标是生成并整合 RCC 中 PNCK 的系统级特征以及 PNCK 小分子抑制剂的基于靶标的激酶分析 通过两个具体目标为未来的化学探针和药物先导物优化计划提供信息。 目标 1 将通过 PNCK 过度表达和敲低生成转录组学和活性激酶组特征 细胞系并通过多组学分析识别 PNCK 驱动的通路和信号网络。目标2将优化 然后使用计算模型和 NanoBRET 靶点表征我们当前的 PNCK 抑制剂 参与后进行激酶分析以评估选择性和脱靶情况。综合起来，系统层面 RCC 中 PNCK 的特征和最佳化合物的基于靶标的激酶谱将进一步阐明 PNCK 在 RCC 中的生物学和治疗潜力，并为后续化学探针和药物先导提供信息 优化项目。 我们的团队结合了计算系统药理学/药物发现方面的互补专业知识 (Schürer)、转化肾癌研究 (Merchan) 和多组学（包括化学蛋白质组学） MIB/MS）癌症激酶组的功能表征（Johnson）成功完成了拟议的 项目目标。