NOVEL IMIDAZOLYL DISULFIDE ANTICANCER AGENTS

迫切需要新的抗癌药物，影响癌症特异性 机制等硫氧还蛋白氧化还原系统是一个重要的调节剂， 癌细胞生长和恶性肿瘤。硫氧还蛋白氧化还原系统是一种 药物开发的独特和新颖的靶点， 抑制癌细胞生长。本建议的总体目标是 检查靶向硫氧还蛋白的新型小分子并确定其 作为抗癌药物的潜在临床前研究。这项I期 我们打算开发一种咪唑基二硫化物抑制剂， 硫氧还蛋白，以便可以考虑用于全规模临床前研究。 这将包括第二阶段的建议。具体目标 （1）测定体内抗肿瘤活性 四种原型2-咪唑基二硫化合物在小鼠中的活性 植入人乳腺、结肠或肾脏异种移植物，（2）确定 先导化合物给药的最佳剂量和时间表 （3）对先导化合物进行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，有助于开发最佳给药方案， 并提供对后期II期毒理学研究至关重要的信息 和临床研究。 拟定商业应用： 在美国，每五个死亡中就有一个是由癌症引起的。总体癌症 美国的毒品市场超过20亿美元。非常需要 鉴定新和选择性的基于小分子的系统性癌症 治疗该建议旨在确定小规模 未来用作乳腺、结肠和肾脏药物的二硫化物化合物 癌

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.