Development of Novel MNK Inhibitors for Treating Glioblastoma

开发治疗胶质母细胞瘤的新型 MNK 抑制剂

基本信息

批准号：
10002320
负责人：
LEONIDAS C. PLATANIAS
金额：
$ 50.12万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10002320
关键词：
Acute Toxicity Tests Adult Binding Brain Neoplasms Cell Proliferation Cell Survival Cell physiology Central Nervous System Neoplasms Clinical Clinical Treatment Complex Crystallization Data Development Drug Design Drug Kinetics Eukaryotic Initiation Factor-4E FMRP Feedback Functional disorder Future Genetic Translation Glioblastoma Glioma Goals Growth Growth Factor Receptors Human In Vitro MAP Kinase Gene Malignant - descriptor Malignant Neoplasms Maximum Tolerated Dose Mediating Modeling Molecular Normal Cell Oncogenic Outcome Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phosphorylation Phosphotransferases Play Property Proteins Radiation therapy Receptor Signaling Research Resistance Role Sampling Structure Therapeutic Toxic effect Translation Initiation Work Xenograft procedure base cancer cell cancer stem cell cell growth efficacy testing experimental study improved in vitro activity in vivo in vivo Model inhibitor/antagonist kinase inhibitor mouse model new therapeutic target novel novel strategies novel therapeutic intervention response standard care stem cell proliferation stem cells targeted agent tool tumor

项目摘要

Glioblastoma (GBM) is most common central nervous system neoplasm in adults and one of the most aggressive and fatal malignancies in humans. The limited number of available therapies almost always fails, due to resistance of GBM stem cells (GSCs). We have found that expression of MNK kinases correlates with GBM grade and overall survival. Our studies demonstrate that these kinases play key and essential roles for survival of GSCs, raising the possibility that MNK targeting may provide a unique approach for the treatment of GBM. The current proposal aims to identify effector mechanisms by which MNK pathways promote GSC survival and to develop novel, specific, and effective MNK inhibitors that could be ultimately developed clinically for the treatment of GBM. Different GBM models and primary samples from GBM patients will be used for that purpose. Aim 1 will define MNK effector pathways in GSCs and will dissect their contributions in GBM pathophysiology. Experiments will be performed to define the roles of MNK-regulated effectors in controlling oncogenic mRNA translation, cell proliferation, and survival of GSCs. In addition, the differential requirement of MNK1 versus MNK2 in GSC growth and survival and their regulatory effects on downstream pathways will be dissected. Aim 2 will develop potent and selective MNK inhibitors through rational medicinal chemistry optimization. For this purpose, optimization of the MNK inhibitors that we have already developed will be pursued to improve potency, selectivity, and pharmaceutical properties. In addition, crystallization studies will be performed to understand the binding mode and support structure-based drug design. Aim 3 will evaluate the effects of MNK inhibition in orthotopic GBM mouse models. Compounds selected for adequate toxicity profiles and pharmacokinetics will be tested for efficacy against GBM using orthotopic xenograft mouse models for GBM. Altogether, the results of this work will provide important information on the mechanisms by which MNK kinases promote survival of GBM stem cells and will drive the development of novel pharmacological agents targeting the MNK kinase pathway for the treatment of GBM.

胶质母细胞瘤（GBM）是成年人中最常见的中枢神经系统肿瘤，也是最具侵略性的中枢神经系统肿瘤之一和人类致命的恶性肿瘤。由于有限的可用疗法几乎总是失败的 GBM干细胞（GSC）的抗性。我们发现MNK激酶的表达与GBM相关等级和整体生存。我们的研究表明，这些激酶起生存的关键和重要作用在GSC中，提高了MNK靶向可能为GBM治疗提供独特的方法的可能性。当前的建议旨在确定MNK途径促进GSC生存和开发新颖，特异性和有效的MNK抑制剂，这些抑制剂最终可以在临床上开发 GBM的处理。 GBM患者的不同GBM模型和主要样本将用于此目的。 AIM 1将在GSC中定义MNK效应途径，并将其在GBM病理生理学中的贡献。将进行实验以定义MNK调节的效应子在控制致癌mRNA中的作用 GSC的翻译，细胞增殖和存活。另外，MNK1与将阐述GSC生长和生存的MNK2及其对下游途径的调节作用。目的 2将通过合理的药物化学优化发展有效和选择性的MNK抑制剂。为了这目的，我们已经开发的MNK抑制剂的优化将被追求以提高效力，选择性和药物特性。此外，将进行结晶研究以了解结合模式和支持基于结构的药物设计。 AIM 3将评估MNK抑制作用原位GBM鼠标模型。选择用于足够毒性特征和药代动力学的化合物将是使用原位异种移植小鼠模型对GBM进行了针对GBM的疗效。总共，结果这项工作将提供有关MNK激酶促进GBM生存的机制的重要信息干细胞并将推动针对MNK激酶途径的新型药理剂的发展用于治疗GBM。