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.

项目摘要 人类激酶组是最成熟的可药用蛋白质家族之一。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焦点， 仍然是被低估的。激酶抑制剂在人类癌症的治疗中发挥重要作用，例如 晚期肾细胞癌（RCC）是一种恶性肿瘤，其发病率不断增加，预后不良。 虽然肾细胞癌的临床结果正在改善酪氨酸激酶抑制剂和免疫治疗，大多数 患者最终死于进行性耐药疾病。我们的长期目标是找到治疗晚期 通过鉴定和验证用于药物开发的新型RCC激酶靶点。 PNCK是一种研究不足的激酶。分析Illuminating the Druggable Genome（IDG）知识门户 Pharos沿着其他资料显示，PNCK是RCC中最差异过表达的激酶 患者，并与更差的疾病特异性生存率相关。在我们的初步研究中， 导致RCC细胞生长和增殖显着增加，而PNCK抑制则直接发挥抗肿瘤作用 通过抑制细胞生长、诱导RCC细胞周期停滞和细胞凋亡以及间接作用， 通过调节血管生成和DNA损伤反应途径的表达。这些发现强调了 PNCK在RCC中的临床和生物学相关性。本提案的目标是生成并整合 肾癌中PNCK的系统水平特征与PNCK小分子抑制剂的靶向激酶谱 通过两个特定目标为未来的化学探针和药物先导优化计划提供信息。 Aim 1将从PNCK过表达和敲低中产生转录组学和活性激酶组签名 细胞系，并通过多组学分析鉴定PNK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靶点来表征我们目前的PNCK抑制剂， 结合，然后进行激酶分析，以评估选择性和脱靶。结合起来，系统级 肾癌中PNCK的特征和最佳化合物的基于靶点的激酶谱将进一步阐明 PNCK在RCC中的生物学和治疗潜力，并为随后的化学探针和药物先导物提供信息 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）功能表征的癌症激酶组（约翰逊），以成功地完成所提出的 项目目标。