STATs as a Novel Approach to Cancer Therapy

STAT 作为癌症治疗的新方法

• 批准号: 6870436
• 负责人: James K Turkson
• 金额: $ 11.25万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-14 至 2005-08-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6870436
• 关键词: DNA binding protein; annexins; antineoplastics; athymic mouse; carcinogenesis inhibitor; chemical models; combinatorial chemistry; drug discovery /isolation; laboratory mouse; neoplastic transformation; peptide analog; polymerization; small molecule; terminal nick end labeling; tissue /cell culture; transcription factor

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

描述（由申请人提供）：信号转导剂和转录激活剂（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，这对于它们在细胞生长和分化、发育、炎症和生存等生理过程中的关键作用非常重要。然而，该转录因子家族的某些成员（特别是 Stat3）的持续激活被发现伴随着恶性转化。在实体瘤和血液肿瘤中，包括乳腺癌、前列腺癌、头颈鳞状细胞癌、黑色素瘤和多发性骨髓瘤，这种持续的 Stat3 活性在肿瘤发生中的因果作用已经确定，从而验证 Stat3 作为临床上重要的癌症靶标药物发现。由于目前没有 Stat3 的直接药理学抑制剂，因此本申请的目标是鉴定有潜力用作癌症治疗的有效小分子 Stat3 抑制剂。我们已经在鉴定一些选择性抑制 Stat3 信号传导的先导化合物方面取得了进展。该申请的中心假设是Stat3信号传导的小分子抑制剂将诱导恶性细胞的生长抑制和凋亡，从而阻止肿瘤生长。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。将开发肽模拟方法来阻止 Stat3 蛋白通过其 SH2 结构域进行二聚化。基于结构的组合方法将用于将先导肽转化为生物活性剂； （2）。评估新型肽模拟物对 Stat3 的有效抑制作用及其在体外和全细胞中的生物学效应。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效应； （3）。评估上述确定的有效化合物在小鼠人类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有效 Stat3 抑制剂，用于最终的临床应用