NOVEL IMIDAZOLYL DISULFIDE ANTICANCER AGENTS

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.