Molecular Mechanisms of G5-7 Allosteric Inhibition of Jak2

Jak2 G5-7变构抑制的分子机制

基本信息

批准号：
8877959
负责人：
KEQIANG YE
金额：
$ 35.69万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-05-04 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8877959
关键词：
Academia Address Applications Grants Automobile Driving Binding Brain Neoplasms Cell Proliferation Cells Clinical Clinical Trials Complex Cytokine Receptors EGF gene EGFR inhibition Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Exhibits Failure Family member Gene Amplification Glioblastoma Glioma Grant Human Industry Interruption Intracranial Neoplasms JAK2 gene Ketones Knowledge Light Malignant - descriptor Malignant Glioma Malignant Neoplasms Modeling Modification Molecular Mutation Nuclear Translocation Oncogenes Oral Administration PTEN gene Paper Patients Phosphorylation Phosphotransferases Play Primary Brain Neoplasms Prolactin Receptor Protein Tyrosine Kinase Recruitment Activity Refractory Regulation Reporting Resistance Role STAT3 gene Science Signal Pathway Signal Transduction Solid Neoplasm Specificity Testing Therapeutic Intervention Treatment Efficacy analog base drug use screening epidermal growth factor receptor VIII inhibitor/antagonist innovation meetings mutant novel pi bond protein protein interaction public health relevance receptor reconstitution resistance mechanism screening small molecule therapeutic development therapeutic target tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Approximately 40~50% of GBMs show amplification of EGFR with most expressing an activated mutant receptor (EGFRvIII) as a driving oncogene, associated with hyper-activation of STAT3. Nonetheless, EGFR inhibition has thus far met with clinical failure, mostly due to PTEN deficiency. The central theme of this RO1 grant application focuses on the molecular mechanism of how the newly identified small molecule G5- 7 selectively inhibits Jak2/EGFR/STAT3 axis and exerts the therapeutic efficacy toward this most malignant GBM. In our preliminary study, we have identified G5-7 via cell-based drug screening using U87MG/EGFRvIII to mimic the genetic alteration in GBM patients with EGFR amplification and PTEN deficiency, and found that this compound exhibits potent anti-GBM activity in an intracranial model. G5-7 binds to FERM domain of Jak2 and blocks EGFR and STAT3 phosphorylation, robustly inhibiting human GBM neurosphere progression. Conceivably, Jak2 might bind to both EGFR and EGFRvIII and allow EGFR to phosphorylate EGFRvIII and induce its nuclear translocation, resulting STAT3 phosphorylation. Our overall hypothesis is that G5-7 disrupts the JAK2/EGFR/EGFRvIII signalsomes, suppressing GBM progression. This grant contains three specific aims that examine the anti-cancer mechanisms by G5-7. This highly integrated effort builds on the important discoveries of this small compound that selectively targets the most malignant GBM that are refractory to all other current therapies. The knowledge from this study will shed light on how allosteric inhibition of Jak2 specifically blocks EGFR/STAT3 axis' signaling cascades. The novel concept that Jak2/EGFR/EGFRvIII plays an essential role in driving GBM progression will provide an innovative therapeutic target for screening new compounds for treating the most devastating brain tumors and other solid tumors.

描述（由应用程序提供）：大约40〜50％的GBM显示了EGFR的扩增，大多数表达活化的突变受体（EGFRVIII）作为驱动癌基因，与STAT3的过度激活有关。尽管如此，迄今为止，EGFR抑制已经遇到临床衰竭，这主要是由于PTEN缺乏症。该RO1赠款应用的中心主题着重于新鉴定的小分子G5- 7如何选择地抑制JAK2/EGFR/STAT3轴的分子机制，并对这种最恶性GBM发挥治疗效率。在我们的初步研究中，我们通过基于细胞的药物筛查使用U87MG/EGFRVIII鉴定了G5-7，以模仿EGFR扩增和PTEN缺乏症的GBM患者的遗传改变，并发现该化合物在脑内模型中表现出潜在的抗GBM活性。 G5-7与JAK2的FERM结构域结合，并阻止EGFR和STAT3磷酸化，可牢固抑制人GBM神经球的进展。可以想象，JAK2可能会与EGFR和EGFRVIII结合，并允许EGFR磷酸化EGFRVIII并影响其核易位，从而导致STAT3磷酸化。我们的总体假设是，G5-7破坏了JAK2/EGFR/EGFRVIII信号，从而抑制了GBM的进展。该赠款包含三个特定的目的，可以通过G5-7检查抗癌机制。这种高度综合的工作是基于这种小型化合物的重要发现，该发现选择性地瞄准了对所有其他当前疗法难治性的最恶性GBM。这项研究的知识将阐明JAK2的变构抑制如何特异性阻断EGFR/STAT3轴的信号级联。 JAK2/EGFR/EGFRVIII在驱动GBM进展中起着至关重要的作用的新颖概念将为筛选新化合物提供创新的治疗靶标，用于治疗最破坏性的脑肿瘤和其他实体瘤。