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

• 批准号: 10431859
• 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
• 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/10431859
• 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; efficacy testing; experimental study; improved; in vitro activity; in vivo; in vivo Model; inhibitor; kinase inhibitor; mouse model; new therapeutic target; novel; novel strategies; novel therapeutic intervention; response; standard care; stem cell growth; stem cell proliferation; stem cell survival; stem cells; targeted agent; tool; tumor

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）是成人最常见的中枢神经系统肿瘤，也是最具侵袭性的肿瘤之一 和致命的恶性肿瘤。有限数量的可用疗法几乎总是失败，由于 GBM干细胞（GSC）的抗性。我们发现MNK激酶的表达与GBM相关， 等级和总体生存率。我们的研究表明，这些激酶对生存起着关键和必要的作用， 这增加了MNK靶向可能为治疗GBM提供独特方法的可能性。 目前的建议旨在确定MNK途径促进GSC存活的效应机制， 开发新的，特异性的，有效的MNK抑制剂，最终可以在临床上开发用于 GBM的治疗不同的GBM模型和GBM患者的原始样本将用于该目的。 目的1将定义GSC中的MNK效应通路，并将剖析它们在GBM病理生理学中的贡献。 将进行实验以确定MNK调节的效应物在控制致癌mRNA中的作用。 GSC的翻译、细胞增殖和存活。此外，MNK 1与 MNK 2在GSC的生长和存活及其对下游通路的调节作用将被解剖。目的 2将通过合理的药物化学优化开发有效的和选择性的MNK抑制剂。为此 为了达到这个目的，将对我们已经开发的MNK抑制剂进行优化，以提高效力， 选择性和药物性质。此外，将进行结晶研究，以了解 基于结合方式和支持结构的药物设计。目的3将评估MNK抑制剂在 原位GBM小鼠模型。将根据适当的毒性特征和药代动力学选择化合物， 使用GBM的原位异种移植小鼠模型测试针对GBM的功效。总的来说， 这项工作将为MNK激酶促进GBM存活的机制提供重要信息 干细胞，并将推动针对MNK激酶途径的新型药理学药物的开发 用于治疗GBM。