In this project we will use combinatorial chemical libraries for the isolation of compounds that are directed at cancer-specific or cancer- related targets and that can be expected to have a growth attenuating effect on cells.
The specific aims are: (1) To characterize RNA-binding compounds isolated from libraries produced by project 2 (aminoglycoside). These compounds are targeted to the fusion points of cancer-specific messenger RNAs and they are designed to interfere with translation and to inhibit tumor growth. These compounds will be selected with a plasmon surface resonance screen and then tested for anti-tumor activity in cell culture. Effective compounds will be advanced to animal tests. (2) To isolate inhibitors of Myc-Max dimerization from libraries produced by project 1 (iminodiacetic acid). Inhibition of dimerization will be tested by a fluorescence resonance energy transfer. The tests will be done either in vitro with fluorescently labeled leucine zippers of Myc and Max or they will be done in cell culture expressing Myc and Max leucine zippers labeled to green fluorescent proteins and its mutant blue fluorescent protein. Effective inhibitors will be tested for anti-tumor activity in cell culture and in animal tumor models. (3) To isolate inhibitors of ERB-b by screening for up-regulation of alpha2/beta1 integrin. By choosing a downstream endpoint of Erb-B2 activity, we propose to screen for inhibitors that act anywhere along the Erb-B signal. Expression of alpha2/beta1 integrin has been linked to the ability of breast cancer cells to differentiate. Therefore, restoration of this integrin is expected to have anti-tumor activity which will be tested in cell culture and, with selected compounds, in the animal.
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