The overall goal of this Program Project is to find a general method for discovering small-molecule ligands that modulate the function of proteins relevant to cancer. In Project 1, we will build million-member libraries of small molecules that mimic natural products in their size, rigidity, complexity in stereochemistry and functional diversity. These molecules will be designed so that the functionalities displayed on the skeleton of molecule are presented in a well-defined way over a large area (>50 A/2). These design principles are derived from a study of natural products known to bind to proteins. The libraries will be constructed on solid phase beads using the split- pool synthesis technique. This approach allows the synthesis of large libraries of molecules (> 10/6 members) in a small number of chemical steps. To use split-pool synthesis to prepared libraries with significant structural and functional diversity, we will develop new synthetic methods, applicable to immobilized substrates, to allow enantioselective reactions in this format. We propose the development of several libraries, including a library based on 1,3-diol derivatives to yield polyketide-related molecules. We will also use the Diels-Alder reactions of N-acylpyridinium salts to yield polycyclic alkaloid-like molecules. Shikimic acid derivatives will be employed as a template in another library, using cycloaddition and ring opening reactions to produce a library of very high structural complexity. Palladium-catalyzed cyclocarbometallation reactions will be used to construct a library of spirocyclic molecules. We will also synthesize """"""""dumbbell"""""""" libraries, in which each member of a library is linked to a ligand of FKBP. To identify new ligands for know classes of proteins, we will construct several libraries based on know ligands. Protein kinase inhibitors will be developed by incorporating purine monomers, and by using enantioselective catalytic ring-opening reactions to produce small molecules similar to the natural product balanol. A library of dolastatin- like compounds will be synthesized to identify gamma-tubulin inhibitors. These libraries will be used in the screens developed in Projects 2 and 3 to discover novel small molecules that affect processes involved in cancer. As we identify new ligands that modulate protein-protein interactions in the screens for cancer drugs described in Projects 2 and 3, we will use this information to guide the design for new libraries.
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