DISCOVERY OF SMALL-MOLECULE MODULATORS OF IL-10 RECEPTOR

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Interleukin-10 (IL-10) is a pleiotropic immunomodulatory cytokine that can both suppress cell-mediated immunity and support antibody- mediated immunity. IL-10 acts by forming multimeric complexes of its target receptors, IL-10R1 and IL-10R2, on the surface of immune cells, thereby initiating specific intracellular signal transduction pathways. IL- 10 has been observed to down-regulate the immune response during the development of tumors, and blocking IL-10 activity increases the ability of mice to reject tumors and prolong their survival rates. A small organic molecule antagonist of IL-10 would be highly valued as a novel anti- cancer treatment. NeoGenesis has developed a combinatorial chemistry- based drug discovery program capable of synthesizing and rapidly screening millions of drug-like molecules to identify small-molecule ligands for any protein target. This project proposes the synthesis of new combinatorial libraries of small organic molecules and the development of novel screening protocols which will identify compounds that can bind with high affinity and specificity to the extracellular domain of the IL- 10R1 receptor. These small-molecule ligands will be tested and optimized for their ability to antagonize IL-10 activities. If this strategy is successful, it will be applied to other high-value drug targets which work by similar mechanisms, such as interferon and other interleukin receptors. PROPOSED COMMERCIAL APPLICATIONS: This project will develop a small-molecule antagonist of interleukin-10, and the technology developed here will be applicable to the development of small-molecule antagonists of other cytokines which function through multimerization of membrane-spanning receptors.