The development and application of the solution-phase synthesis of combinatorial libraries for screening in novel assays designed to identify new agents for the treatment of cancer are detailed. Employing N-BOC iminodiacetic acid and a series of structurally diverse but related anhydride-based templates and a 3 or 4 step synthetic protocol including a liquid-liquid or liquid-solid extraction at each step for purification (greater than or equal to 95% pure irrespective of reaction efficiency), chemical or combinatorial libraries of small organic molecules will be prepared in a variety of formats for screening. This includes formats capable of the parallel synthesis of individual pure compounds (1000 member libraries, individual compounds), the mixed synthesis of modest sized libraries composed of small mixtures (1000-10,000 member libraries, 10-100 compounds mixture), or the combinatorial synthesis of large libraries (25,000-1,000,000 member libraries, 10,000-30,000 compounds/mixture). All are produced on a scale that provides 50-150 mg of the final materials (greater than or equal to 95% pure) suitable for broad screening and the libraries are especially suited for targeting the protein-protein interactions involved in cellular signaling. Consequently, they will be screened against all targets in this RFA application and will be available for future target screening as well. Our own efforts will focus on the discovery and development of antagonists of erbB-2 receptor dimerization and activation, antagonists of Myc-Max heterodimerization and the resulting transcription activation, and RGD mimetics as inhibitors of angiogenesis.
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