DISCOVERY OF SMALL-MOLECULE MODULATORS OF IL-10 RECEPTOR

白介素10(IL-10)是一种多效性免疫调节细胞因子，既能抑制细胞免疫，又能支持抗体免疫。IL-10通过在免疫细胞表面形成其靶受体IL-10R1和IL-10R2的多聚体而发挥作用，从而启动特定的细胞内信号转导途径。IL-10已被观察到在肿瘤发展过程中下调免疫反应，阻断IL-10活性可提高小鼠排斥肿瘤的能力，延长其存活率。作为一种新型的抗癌药物，IL-10的有机小分子拮抗剂具有很高的应用价值。NeoGenesis开发了一种基于组合化学的药物发现计划，能够合成和快速筛选数百万个类药物分子，以识别任何蛋白质靶标的小分子配体。该项目建议合成新的有机小分子组合文库，并开发新的筛选方案，以鉴定与IL-10R1受体胞外区具有高亲和力和特异性的化合物。这些小分子配体将被测试和优化它们对抗IL-10活性的能力。如果这一策略成功，它将应用于其他通过类似机制发挥作用的高价值药物靶点，如干扰素和其他白细胞介素受体。建议的商业应用：该项目将开发一种白细胞介素10的小分子拮抗剂，这里开发的技术将适用于开发其他细胞因子的小分子拮抗剂，这些小分子拮抗剂通过跨膜受体的多聚体发挥作用。

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.