STATs as a Novel Approach to Cancer Therapy

描述（由申请人提供）：信号转导和转录激活因子（STAT）蛋白家族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蛋白仅被瞬时激活，这对于它们在生理过程中的关键作用是重要的，包括细胞生长和分化、发育、炎症和存活。然而，已发现该转录因子家族的某些成员，特别是Stat 3的持续激活伴随恶性转化。在实体瘤和血液肿瘤中，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，已经确定了这种持续的Stat 3活性在肿瘤发生中的因果作用，从而验证了Stat 3作为癌症药物发现的临床重要靶点。由于目前没有Stat 3的直接药理学抑制剂，因此本申请的目的是鉴定具有用作癌症治疗剂的潜力的有效小分子Stat 3抑制剂。我们已经在鉴定一些选择性抑制Stat 3信号传导的先导化合物方面取得了进展。本申请的中心假设是Stat 3信号传导的小分子抑制剂将诱导恶性细胞中的生长抑制和凋亡，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Stat 3二聚化、DNA结合和致癌信号传导的小分子抑制剂。拟肽方法将被开发以阻断Stat 3蛋白通过其SH 2结构域的二聚化。基于结构和组合的方法将用于将先导肽转化为生物活性剂;（2）。评价新型肽模拟物对Stat 3的有效抑制作用及其体外和全细胞生物学效应。体外DNA结合活性和基于细胞的报告基因测定将用于筛选化合物。软琼脂生长、TUNEL测定和膜联蛋白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在小鼠人肿瘤模型中的抗肿瘤作用。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强效Stat 3抑制剂，用于最终的临床应用

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