Targeting the HuR Oncogenic Role with a New Class of Cytoplasmic Dimerization Inhibitors.
Targeting the HuR Oncogenic Role with a New Class of Cytoplasmic Dimerization Inhibitors.
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用一类新的细胞质二聚化抑制剂靶向HuR致癌作用。
DOI：
10.1158/0008-5472.can-20-2858
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发表时间：
2021-04-15
期刊：
影响因子：
11.2
通讯作者：
Nabors LB
中科院分区：
文献类型：
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作者：
Filippova N;Yang X;Ananthan S;Calano J;Pathak V;Bratton L;Vekariya RH;Zhang S;Ofori E;Hayward EN;Namkoong D;Crossman DK;Crowley MR;King PH;Mobley J;Nabors LB
新型治疗方法的发展利用上游调节因子突变引起的关键细胞信号通路激活状态的改变，已经产生了个性化医疗领域。这些第一代的努力集中在通过大量肿瘤样本的深度测序确定的可操作突变上。我们提出，利用下游关键的“控制节点”存在第二代机会，这些节点有助于肿瘤的发生，并且由于上游调节和微环境影响的丧失而被不适当地激活。rna结合蛋白HuR代表了这样一个节点。由于癌细胞中的HuR功能依赖于HuR二聚化及其核/细胞质穿梭，我们开发了一类新的靶向HuR蛋白二聚化的分子。结构-活性关系算法使HuR多聚体形成抑制剂的开发成为可能，这些抑制剂可溶，具有微摩尔活性，并能穿透血脑屏障（BBB）。这些抑制剂在基于细胞的HuR二聚化检测中被评估为活性验证和特异性。SRI-42127是一种符合这些标准的分子，可抑制原发性患者源性胶质母细胞瘤（PDGx） xenolines中HuR多聚体的形成，从而阻止增殖、诱导凋亡和抑制集落形成。在小鼠模型中，SRI-42127具有良好的中枢神经系统渗透特性和抑制肿瘤生长的作用。sri -42127处理的PDGx xenolines在胶质母细胞瘤分子亚型中的RNA和蛋白质分析证实了HuR上调的靶标的衰减。这些结果强调了如何关注HuR促进癌症进展的关键属性，即细胞质定位和多聚化，从而开发出一种新型的高效抑制剂。
The development of novel therapeutics that exploit alterations in the activation state of key cellular signaling pathways due to mutations in upstream regulators has generated the field of personalized medicine. These first-generation efforts have focused on actionable mutations identified by deep sequencing of large numbers of tumor samples. We propose that a second-generation opportunity exists by exploiting key downstream “nodes of control” that contribute to oncogenesis and are inappropriately activated due to loss of upstream regulation and microenvironmental influences. The RNA-binding protein HuR represents such a node. Since HuR functionality in cancer cells is dependent on HuR dimerization and its nuclear/cytoplasmic shuttling, we developed a new class of molecules targeting HuR protein dimerization. A structure-activity relationship algorithm enabled development of inhibitors of HuR multimer formation that were soluble, had micromolar activity, and penetrated the blood-brain-barrier (BBB). These inhibitors were evaluated for activity validation and specificity in a robust cell-based assay of HuR dimerization. SRI-42127, a molecule that met these criteria, inhibited HuR multimer formation across primary patient-derived glioblastoma (PDGx) xenolines, leading to arrest of proliferation, induction of apoptosis, and inhibition of colony formation. SRI-42127 had favorable attributes with central nervous system penetration and inhibited tumor growth in mouse models. RNA and protein analysis of SRI-42127-treated PDGx xenolines across glioblastoma molecular subtypes confirmed attenuation of targets upregulated by HuR. These results highlight how focusing on key attributes of HuR that contribute to cancer progression, namely cytoplasmic localization and multimerization, has led to the development of a novel, highly effective inhibitor.