Development of Novel MNK Inhibitors for Treating Glioblastoma

摘要胶质母细胞瘤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。 以及致命的人类恶性肿瘤。可用疗法的有限数量几乎总是失败的，因为 基底膜干细胞(GSCs)的耐药性。我们发现MNK激酶的表达与基底膜相关。 等级和总体存活率。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提供一种独特方法的可能性。 目前的建议旨在确定MNK通路促进GSC存活和 开发新的、特异的、有效的MNK抑制剂，最终可用于临床治疗 基底膜的治疗。为此，将使用不同的GBM模型和来自GBM患者的原始样本。 目标1将定义GSCs中的MNK效应通路，并剖析它们在GBM病理生理学中的作用。 将进行实验，以确定MNK调节的效应器在控制致癌mRNA中的作用 GSCs的翻译、细胞增殖和存活。此外，MNK1与MNK1的差异要求 将解剖MNK2在GSC生长和存活中的作用及其对下游通路的调控作用。目标 2通过合理的药物化学优化，开发高效、选择性的MNK抑制剂。为了这个 目的，将对我们已经开发的MNK抑制剂进行优化，以提高效力， 选择性和药用性能。此外，还将进行结晶研究，以了解 结合方式和支撑结构为主的药物设计。AIM 3将评估MNK抑制对小鼠心脏功能的影响 同种异体GBM小鼠模型。选择具有适当毒性和药代动力学特征的化合物 使用GBM的原位异种移植小鼠模型测试抗GBM的有效性。总而言之， 这项工作将为MNK激酶促进基底膜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药物的开发 用于治疗基底膜。

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.