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：
10650358
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/10650358
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 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 Phosphorylation Phosphotransferases Play Property Proteins Radiation therapy Receptor Signaling Research Resistance Role Sampling Structure Therapeutic Toxic effect Translation Initiation Work Xenograft procedure cancer cell cancer stem cell clinical translation efficacy testing experimental study improved in vitro activity in vivo in vivo Model inhibitor kinase inhibitor mRNA Translation mouse model new therapeutic target novel novel strategies novel therapeutic intervention pharmacologic response standard care stem cell growth stem cell proliferation stem cell survival 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.