Discovery of DNA Binding Anticancer Drugs That Target Oncogenic Transcription Factors Associated With Human Breast Cancer.

摘要

This proposal is designed to develop sequence specific DNA binding polyamides as an approach for specifically inhibiting Her2/neu expression, a gene that is over expressed in human breast cancers. The approach is to design polyamides that are optimized for targeting the binding of ESX a transcription factor which up regulates Her2/neu by binding to its consensus site within the Her2/neu promoter. Active agents are tested for their ability to inhibit Her2/ neu expression in both cell free and cellular systems. A number of polyamides were identified as being effective inhibitors of ESX complex formation and their ability to block complexes was analyzed in detail. None of the agents were effective at preventing expression in cells. A series of fluorescently labeled polyamides representing structural diverse compounds were tested for their ability to localize in the nucleus of live cells. No agent was found to localize in the nucleus even at relatively high concentrations or for incubations times up to several days. Studies are underway to develop a new generation of polyamides that posses not only the ability to effectively target the Her2/neu promoter under cell free conditions but also to function effectively on nuclear DNA targets in intact cells.