Dual STAT3/NF-kB Inhibitors for Targeted Cancer Therapy

描述(由申请人提供)：尽管我们在了解癌细胞生物学方面取得了所有进展，但晚期癌症治疗的基石仍然是非特异性细胞毒药物。挑战是确定癌细胞恶性行为背后的关键分子靶点，并直接针对这些靶点。由于癌细胞的表型在很大程度上是由细胞中表达的基因模式决定的，因此人们关注的焦点是转录因子的不适当激活，这些转录因子调节控制细胞增殖、存活、自我更新和侵袭的基因。两个这样的致癌转录因子是STAT3和NF-kB。通过我们对开发这些蛋白的靶向抑制剂的研究，我们发现当STAT3的功能被小分子抑制剂阻断时，NF-kB的活性往往会增加。这种核因子-kB活性的增加减弱了STAT3抑制剂对癌细胞的影响，并提出了一些关于这些蛋白质之间的分子和功能相互作用的重要机制问题。为了将这些发现用于癌症治疗，我们着手开发能够同时阻断STAT3和NF-kB作用的化合物。通过对大约200,000种化合物的高通量细胞筛选，以及相关的合成化学工作，我们已经鉴定出两种化合物，它们都能特异性地阻断这两种转录因子。这些STAT3/NF-kB双重抑制剂可能代表了一种独特的癌症治疗策略。我们现在建议在这些观察的基础上进一步了解癌细胞中STAT3和NF-kB之间的相互作用，并阐明这些双重抑制物在癌症治疗中的潜力。针对乳腺癌和多发性骨髓瘤这两种常见的STAT3和核因子-kB共激活的肿瘤，我们将追求三个目标：(1)明确癌细胞中STAT3抑制和核因子-kB激活之间的关系。(2)阐明STAT3/NF-kB双重抑制剂对肿瘤细胞的分子作用。(3)在细胞培养和动物模型中评价STAT3/NF-kB双抑制剂对肿瘤细胞生物学的影响。晚期癌症非常需要针对驱动这些细胞恶性行为的分子缺陷的创新治疗方法。这项工作的最终目标是阐明STAT3和NF-kB在癌细胞中所起的作用，并确定同时针对这两种蛋白作为癌症患者分子治疗形式的可能性。

DESCRIPTION (provided by applicant): For all of our advances in understanding the biology of a cancer cell, the cornerstone of therapy for advanced cancers remains drugs that are non-specifically cytotoxic. The challenge is to identify key molecular targets that underlie the malignant behavior of a cancer cell, and to target these directly. Since the phenotype of a cancer cell is largely driven by the pattern of genes expressed in the cell, much attention has focused on the inappropriate activation of transcription factors that regulate genes controlling proliferation, survival, self-renewal, and invasion. Two such oncogenic transcription factors are STAT3 and NF-kB. Through our research on developing targeted inhibitors of these proteins we have found that when STAT3 function is blocked by small molecule inhibitors, the activity of NF-kB often increases. This increase in NF-kB activity attenuates the effect of STAT3 inhibitors on cancer cells and raises a number of important mechanistic questions about the molecular and functional interaction between these proteins. To exploit these findings for cancer therapy, we set out to develop compounds that could simultaneously block the effects of STAT3 and NF-kB. Through a high throughput cell-based screen of approximately 200,000 compounds, and a related synthetic chemistry effort, we have identified two compounds that specifically block both of these transcription factors. These dual STAT3/ NF-kB inhibitors may represent a unique strategy for cancer therapy. We now propose to build on these observations to further understand the interaction between STAT3 and NF-kB in cancer cells, and to elucidate the potential for these dual inhibitors in the treatment of cancer. Focusing on breast cancer and multiple myeloma, tumors that frequently display co-activation of STAT3 and NF-kB, three aims will be pursued: (1) To discern the relationship between STAT3 inhibition and NF-kB activation in cancer cells. (2) To elucidate the molecular effects of dual STAT3/ NF-kB inhibitors in cancer cells. (3) To assess the effects of dual STAT3/ NF-kB inhibitors on the biology of cancer cells in cell culture and animal models. There is a great need for innovative treatments for advanced cancer that are targeted to the molecular defects driving the malignant behavior of these cells. The ultimate goal of this work is to elucidate the role that STAT3 and NF-kB are playing in cancer cells, and to determine the potential of simultaneously targeting both proteins as a form of molecular therapy for patients with cancer.