NOVEL IMIDAZOLYL DISULFIDE ANTICANCER AGENTS

迫切需要影响癌症特异性的新的抗癌药物 机械装置。硫氧还蛋白氧化还原系统是一种重要的 癌细胞的生长和恶性程度。硫氧还蛋白氧化还原系统是一种 独特而新颖的靶点选择性地开发药物 抑制癌细胞生长。这项提议的总体目标是 检测以硫氧还蛋白为靶点的新型小分子并确定其 在临床前研究中具有作为抗癌药物的潜力。在此阶段I 我们打算开发一种咪唑基二硫化物抑制剂 硫氧还蛋白，因此它可以被认为是全面的临床前 发展，这将包括第二阶段的提案。具体目标 建议如下：(1)体内抗癌活性的测定 四种原型2-咪唑基二硫化合物在小鼠体内的活性 植入人类乳房、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程序 以及，(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浓度是否可以 在小鼠身上获得，有助于制定最佳给药方案， 并提供对后期第二阶段毒理学至关重要的信息 以及对这些化合物的临床研究。 建议的商业应用： 在美国，每五个人中就有一个死于癌症。整体癌症 美国药品市场规模超过20亿美元。有很大的需要 识别新的和选择性的系统性小分子癌症 治疗。这项建议旨在确定Small的可行性 二硫化合物，未来用作乳房、结肠和肾脏的药物 癌症。

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.