The combined efforts of chemists and biologists are mobilized in this program project aimed at obtaining novel therapeutic drugs for cancer from combinatorial chemical libraries. Four kinds of libraries will be generated and tested. (i) Iminodiacetic libraries are expected to yield compounds that affect protein interactions. (ii) Aminoglycoside libraries have been shown to contain sequence specific RNA binding molecules. (iii) Calicheamicin based oligosaccharide synthetics will be designed for sequence-specific DNA binding and (iv) Epothilone based libraries will be sources of new tubulin interacting substances. Chemical and biological screens will be tested to extract compounds from these libraries that interact with cancer-specific and cancer-related targets. The cancer-specific targets selected for these studies are the fusion regions of chimeric mRNAs generated by cancer-specific chromosomal translocations. These same regions will also be targeted in the form of DNA with the oligosaccharide based sequence-specific binders. Cancer related targets are the dimerization surfaces of the Myc protein and its partner Max. Myc-Max dimers are important stimulators of normal and aberrant cell growth. The alphavbeta3 integrin is the target for inhibitors of tumor angiogenesis, and induction of the integrin alpha2beta1 expression will be used as a readout for an inhibition of the Erb-B2 signaling pathway. The synergy generated by the lively and intense interactions between chemists and biologists will be an important ingredient in the success of this program project.
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