Molecular Mechanisms of G5-7 Allosteric Inhibition of Jak2

 描述(申请人提供)：大约40%~50%的GBM显示EGFR的扩增，其中大多数表达激活的突变受体(EGFRvIII)作为驱动癌基因，与STAT3的过度激活有关。尽管如此，到目前为止，EGFR抑制已在临床上遭遇失败，主要原因是PTEN缺乏。这项RO1赠款申请的中心主题集中在新发现的小分子G5-7如何选择性抑制JAK2/EGFR/STAT3轴并对这种最恶性的GBM发挥治疗效果的分子机制。在我们的初步研究中，我们通过使用U87 MG/EGFRvIII进行基于细胞的药物筛选来鉴定G5-7，以模拟患有EGFR扩增和PTEN缺陷的GBM患者的基因变化，并在颅内模型中发现该化合物具有强大的抗GBM活性。G5-7结合JAK2的FERM结构域，阻断EGFR和STAT3的磷酸化，有力地抑制人GBM神经球的进展。可以想象，JAK2可能同时与EGFR和EGFRvIII结合，并允许EGFR磷酸化EGFRvIII并诱导其核转位，从而导致STAT3磷酸化。我们的总体假设是，G5-7扰乱JAK2/EGFR/EGFRvIII信号体，抑制GBM进展。这项拨款包含三个具体目标，旨在研究G5-7的抗癌机制。这一高度整合的努力建立在这种小化合物的重要发现基础上，这种化合物选择性地针对最恶性的基底膜，而这些基底膜对所有其他目前的治疗方法都是难治的。这项研究的知识将有助于阐明JAK2的变构抑制如何特异性地阻断EGFR/STAT3轴的信号级联反应。JAK2/EGFR/EGFRvIII在推动GBM进展中发挥重要作用的新概念将为筛选治疗最具破坏性的脑肿瘤和其他实体肿瘤的新化合物提供一个创新的治疗靶点。

 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.