STATs as a Novel Approach to Cancer Therapy

描述（由申请人提供）：信号传感器和转录激活因子（STAT）家族蛋白最初是在细胞对细胞因子和生长因子的反应中发现的。在正常细胞中，STAT蛋白仅被短暂激活，这对于其在细胞生长和分化、发育、炎症和生存等生理过程中的关键作用至关重要。然而，该转录因子家族的某些成员，特别是Stat3的持续激活，已被发现伴随着恶性转化。在实体肿瘤和血液系统肿瘤中，包括乳腺癌、前列腺癌、头颈部鳞状细胞癌、黑色素瘤和多发性骨髓瘤，Stat3持续活性在肿瘤发生中的因果作用已经确立，从而验证了Stat3作为癌症药物发现的临床重要靶点。由于目前还没有Stat3的直接药理抑制剂，本应用程序的目标是确定有效的小分子Stat3抑制剂，有可能用作癌症治疗药物。我们已经在确定一些选择性抑制Stat3信号传导的先导化合物方面取得了进展。本应用的中心假设是Stat3信号的小分子抑制剂会诱导恶性细胞的生长抑制和凋亡，从而阻断肿瘤生长。该假设将通过以下具体目标来解决：(1)。开发Stat3二聚化、dna结合和致癌信号传导的小分子抑制剂。拟肽方法将通过Stat3蛋白的SH2结构域来阻断其二聚化。基于结构和组合的方法将用于将铅肽转化为生物活性物质；(2）. 评价新型拟肽制剂对Stat3的有效抑制作用及其在体外和全细胞内的生物学效应。体外DNA结合活性和基于细胞的报告基因检测将用于筛选化合物。软琼脂生长、TUNEL试验和Annexin V-FITC染色将测量化合物的生物学效应；(3)。评价上述有效化合物对小鼠肿瘤模型的抗肿瘤作用。研究将评估这些化合物对肿瘤的毒性和功效程度。拟议的研究将完善和进一步开发先导化合物，作为具有抗肿瘤活性的有效Stat3抑制剂，最终用于临床应用

DESCRIPTION (provided by applicant): Signal Transducer and Activator of Transcription (STAT) family of proteins were originally discovered in context of cellular responses to cytokines and growth factors. In normal cells, STAT proteins are only transiently activated, which is important for their key roles in physiological process, including cell growth and differentiation, development, inflammation and survival. However, persistent activation of certain members of this family of transcription factors, particularly Stat3, has been found to accompany malignant transformation. In both solid and hematological tumors, including breast cancer, prostate cancer, head and neck squamous cell carcinomas, melanoma and multiple myeloma, a causal role for this persistent Stat3 activity in oncogenesis has been established, thereby validating Stat3 as a clinically important target for cancer drug discovery. Since currently there are no direct pharmacological inhibitors of Stat3, the goal of this application is to identify potent small molecule Stat3 inhibitors with the potential to be used as cancer therapeutics. We have already made progress in identifying a number of lead compounds selective for inhibition of Stat3 signaling. The central hypothesis of this application is that small-molecule inhibitors of Stat3 signaling will induce growth inhibition and apoptosis in malignant cells, and thereby block tumor growth. The hypothesis will be addressed by the following Specific Aims: (1). To develop small-molecule inhibitors of Stat3 dimerization, DNA-binding and oncogenic signaling. Peptidomimetic approaches will be developed to block dimerization of Stat3 proteins though their SH2 domains. Structure-based and combinatorial methods will be used to convert lead peptides into biologically active agents; (2). To evaluate novel peptidomimetics for potent inhibitory effects against Stat3 and its biological effects in vitro and in whole cells. In vitro DNA binding activity and cell-based reporter assays will be used for screening of compounds. Soft-agar growth, TUNEL assay, and Annexin V-FITC staining will measure biological effects of compounds; (3). To evaluate the antitumor effects of potent compounds identified above in human tumor models in mice. Studies will assess toxicity and degree of efficacy of these compounds against tumors. The proposed studies will refine and further develop lead compounds as potent Stat3 inhibitors with antitumor activities for eventual clinical applications