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）：最初在细胞对细胞因子和生长因子的细胞反应中发现了转录（Stat）蛋白质家族的信号换能器和激活因子（STAT）。在正常细胞中，STAT蛋白仅被暂时激活，这对于它们在生理过程中的关键作用很重要，包括细胞生长和分化，发育，炎症和存活。但是，发现该转录因子家族的某些成员（尤其是STAT3）的持续激活伴随着恶性转化。在固体和血液学肿瘤中，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，这种持续性STAT3活性在肿瘤发生中的因果作用，从而将STAT3验证为临床上重要的癌症药物发现靶标。由于目前没有STAT3的直接药理抑制剂，因此该应用的目的是鉴定有效的小分子STAT3抑制剂，其潜力被用作癌症治疗剂。我们已经在确定许多铅化合物选择性抑制STAT3信号传导方面取得了进展。该应用的中心假设是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，从而阻止肿瘤的生长。该假设将通过以下特定目的来解决：（1）。开发STAT3二聚化，DNA结合和致癌信号的小分子抑制剂。将开发肽类似方法，以通过其SH2结构域阻止STAT3蛋白的二聚化。基于结构的和组合方法将用于将铅肽转化为生物活性剂。 （2）。评估新型肽仪对STAT3及其在体外和整个细胞中的生物学作用的有效抑制作用。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。软性生长，TUNEL分析和膜联蛋白V-FITC染色将测量化合物的生物学作用； （3）。评估上面在小鼠中人类肿瘤模型中鉴定出的有效化合物的抗肿瘤作用。研究将评估这些化合物对肿瘤的毒性和疗效程度。拟议的研究将完善并进一步开发铅化合物，作为具有抗肿瘤活性的有效STAT3抑制剂，以最终进行临床应用