Interleukin-4 (IL-4) is a multifunctional cytokine and an important regulator of inflammation. When deregulated, IL-4 activity is associated with asthma, allergic inflammation, and multiple types of cancer. While antibody-based inhibitors targeting the soluble cytokine have been evaluated clinically, they failed to achieve their end points in trials. Small-molecule inhibitors are an attractive alternative, but identifying effective chemotypes that inhibit the protein–protein interactions between cytokines and their receptors remains an active area of research. As a result, no small-molecule inhibitors to the soluble IL-4 cytokine have yet been reported. Here, we describe the first IL-4 small-molecule inhibitor identified and characterized through a combination of binding-based approaches and cell-based activity assays. The compound features a nicotinonitrile scaffold with micromolar affinity and potency for the cytokine and disrupts type II IL-4 signaling in cells. Small-molecule inhibitors of these important cell-signaling proteins have implications for numerous immune-related disorders and inform future drug discovery and design efforts for these challenging protein targets.

中文翻译：

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细胞因子白介素4的小分子抑制剂。

白介素-4（IL-4）是一种多功能细胞因子，是炎症的重要调节剂。解除调节后，IL-4活性与哮喘，过敏性炎症和多种癌症相关。尽管已经针对靶向可溶性细胞因子的基于抗体的抑制剂进行了临床评估，但它们在试验中未能达到其终点。小分子抑制剂是一种有吸引力的替代品，但是确定抑制细胞因子与其受体之间蛋白质相互作用的有效化学型仍然是研究的活跃领域。结果，尚未报道可溶性IL-4细胞因子的小分子抑制剂。在这里，我们描述了第一个IL-4小分子抑制剂，该抑制剂通过结合方法和细胞活性分析相结合而鉴定和表征。该化合物具有烟酰胺骨架，对细胞因子具有微摩尔亲和力和效力，并破坏细胞中的II型IL-4信号传导。这些重要的细胞信号蛋白的小分子抑制剂对许多与免疫有关的疾病具有影响，并为这些具有挑战性的蛋白靶标的未来药物发现和设计工作提供了信息。