NOVEL IMIDAZOLYL DISULFIDE ANTICANCER AGENTS

新型咪唑基二硫化物抗癌剂

• 批准号: 2775916
• 负责人: ANDREAS VOGT
• 金额: $ 9.8万
• 依托单位: PROLX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2775916
• 关键词: SCID mouse; antineoplastics; breast neoplasms; colon neoplasms; cytotoxicity; dosage; drug design /synthesis /production; drug screening /evaluation; high performance liquid chromatography; imidazole; kidney neoplasms; pharmacokinetics; sulfides; thioredoxin; tissue /cell culture

There is an urgent need for new anticancer drugs affecting cancer specific mechanisms. The thioredoxin redox system is an important regulator of cancer cell growth and malignancy. The thioredoxin redox system is a unique and novel target for the development of drugs to selectively inhibit cancer cell growth. The overall objective of this proposal is to examine novel small molecules that target thioredoxin and determine their potential as anticancer agents with preclinical studies. In this Phase I proposal we intend to develop an imidazolyl disulfide inhibitor of thioredoxin so that it can be considered for full scale preclinical development, which would encompass a Phase II proposal. The Specific Aims of the proposal are as follows: (1) To determine the in vivo antitumor activity of four prototype 2-imidazolyl disulfide compounds in mice implanted with human breast, colon, or renal xenografts, (2) To determine the optimum doses and schedule for administration of the lead compound and, (3) To conduct initial pharmacokinetic studies of the lead compound. These studies will establish whether in vitro cytotoxic concentrations can be obtained in mice, aid in the development of optimum dosing schedules, and provide information that is essential for later Phase II toxicology and clinical studies of the compounds. PROPOSED COMMERCIAL APPLICATION: One in every five deaths in the US is due to cancer. The overall cancer drug market exceeds $2 billion in the USA. There is a significant need to identify novel and selective systemic small molecule-based cancer therapies. This proposal seeks to determine the feasibility of small disulfide compounds for future use as drugs for breast, colon and renal cancer.

迫切需要影响癌症特异性的新抗癌药物 机制。硫氧还蛋白氧化还原系统是重要的调节因子 癌细胞生长和恶性肿瘤。硫氧还蛋白氧化还原系统是 开发药物的独特而新颖的靶标，选择性地 抑制癌细胞生长。该提案的总体目标是 检查靶向硫氧还蛋白的新型小分子并确定其 通过临床前研究表明其具有作为抗癌药物的潜力。在这个第一阶段 我们打算开发一种咪唑基二硫化物抑制剂 硫氧还蛋白，因此可以考虑用于全面的临床前研究 开发，其中将包含第二阶段提案。具体目标 该提案的内容如下： (1)确定体内抗肿瘤活性 四种原型 2-咪唑基二硫化物化合物在小鼠中的活性 植入人类乳腺、结肠或肾脏异种移植物，(2) 确定 先导化合物的最佳剂量和给药方案 (3) 进行先导化合物的初步药代动力学研究。 这些研究将确定体外细胞毒性浓度是否可以 在小鼠中获得，有助于制定最佳给药方案， 并提供对后期 II 期毒理学至关重要的信息 以及化合物的临床研究。 拟议的商业应用： 在美国，五分之一的死亡是由于癌症造成的。总体癌症 美国的药品市场超过20亿美元。非常有必要 识别新型和选择性的系统性小分子癌症 疗法。该提案旨在确定小型项目的可行性 未来用作乳腺、结肠和肾药物的二硫化合物 癌症。