Discovery of a Small-Molecule Inhibitor of Interleukin 15: Pharmacophore-Based Virtual Screening and Hit Optimization

Interleukin (IL)-15 is a pleiotropic cytokine, which is structurally close to IL-2 and shares with it the IL-2 β and γ receptor (R) subunits. By promoting the activation and proliferation of NK, NK-T, and CD8+ T cells, IL-15 plays important roles in innate and adaptative immunity. Moreover, the association of high levels of IL-15 expression with inflammatory and autoimmune diseases has led to the development of various antagonistic approaches targeting IL-15. This study is an original approach aimed at discovering small-molecule inhibitors impeding IL-15/IL-15R interaction. A pharmacophore and docking-based virtual screening of compound libraries led to the selection of 240 high-scoring compounds, 36 of which were found to bind IL-15, to inhibit the binding of IL-15 to the IL-2Rβ chain or the proliferation of IL-15-dependent cells or both. One of them was selected as a hit and optimized by a structure–activity relationship approach, leading to the first small-molecule IL-15 inhibitor with sub-micromolar activity.白细胞介素-15（Interleukin (IL)-15）是一种多效性细胞因子，其结构与白细胞介素-2（IL-2）相近，且二者共享IL-2的β和γ受体亚基。通过促进自然杀伤（NK）细胞、自然杀伤T（NK-T）细胞以及CD8阳性T细胞的活化与增殖，IL-15在固有免疫与适应性免疫中发挥重要作用。此外，IL-15的高表达与炎症性及自身免疫性疾病相关，这推动了多种针对IL-15的靶向拮抗策略的开发。本研究采用原创性研究思路，旨在筛选可阻碍IL-15与IL-15受体结合的小分子抑制剂。通过对化合物库开展基于药效团与分子对接的虚拟筛选，最终筛选得到240个高评分化合物，其中36个可结合IL-15、抑制IL-15与IL-2Rβ链的结合，或抑制IL-15依赖细胞的增殖，或同时兼具上述两种活性。研究选取其中一个活性化合物作为命中化合物，并通过构效关系研究进行优化，最终得到首个具有亚微摩尔级活性的小分子IL-15抑制剂。