DISCOVERY OF PEPTIDE ANTICANCER DRUGS

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Our long-range objective of this proposed NCDDG Cooperative Agreement is to identify and develop synthetic peptides which have major antitumor activity against common and often refractory forms of cancer including cancers of the breast, prostate, lung, colon, and melanoma, and drug-resistant leukemias and lymphomas. The scientific basis for this proposal is a new "breakthrough" technology for rapidly producing and screening large libraries comprised of millions of synthetic peptides produced via a novel random synthesis technique which produces single peptide entities on individual solid phase beads. This capability to produce such libraries has been coupled to rapid techniques to screen the libraries with two complementary strategies. The first technique involves direct molecular probing against cancer-associated receptors such as the Epidermal Growth Factor Receptor, and p185 HER2/neu. The second technique employs libraries specially designed to permit peptides to be tested in solution against relevant human cancer cell lines. The synthetic procedures used to produce the libraries are very versatile and permit incorporation of D as well as L amino acids, or other designer amino acids, and permit the creation of libraries with defined conformational constraints including cyclic peptides. Once peptides are identified which bind to the natural ligand acceptor site in cancer-associated receptors, or which selectively inhibit the in vitro growth of tumor cells, the relevant peptides on the "active beads" will be sequenced and resynthesized for binding affinity, biochemical and biologic studies. Using molecular modeling and peptide conformational and topographical constraining techniques, drug leads will be converted into candidate peptide drugs with favorable pharmacokinetic properties. The candidate drugs are then tested in both in vitro and in vivo tumor systems with the relevant human tumor (e.g. in SCID mice). Active compounds will also be provided to the NCI on a discrete basis for testing through its screening program. The feasibility of our approach has already been established in initial experiments wherein libraries containing at least 2.5 million peptides have been synthesized and from which individual peptides from active beads have been isolated with cancer- receptor binding activity, or inhibition of cancer cell growth. We therefore believe that the potential for discovery of major new anti-tumor agents with this approach by the scientific team assembled is extremely promising.