Galectin-3 has been identified as a critical player in driving the neuroinflammatory responses in Alzheimer’s disease (AD). A key feature of this function of galectin-3 is associated with its interaction with the triggering receptor expressed on myeloid cells-2 (TREM2). Herein, we report a high-throughput screening (HTS) platform that can be used for the identification of inhibitors of TREM2 and galectin-3 interaction. We have utilized this HTS assay to screen a focused library of compounds optimized for the central nervous system (CNS)-related diseases. MG-257 was identified from this screen as the first example of a small molecule that can attenuate TREM2 signaling based on its high affinity to galectin-3 (endogenous ligand of TREM2). Remarkably, MG-257 reduced the levels of proinflammatory cytokines in activated microglial cells, which highlights its ability to inhibit the neuroinflammatory response associated with AD.

中文翻译：

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喹啉-吡唑支架作为 Galectin-3 的新型配体和 TREM2 信号的抑制剂。

Galectin-3 已被确定为驱动阿尔茨海默病 (AD) 神经炎症反应的关键参与者。半乳糖凝集素 3 的这一功能的一个关键特征与其与髓样细胞 2 (TREM2) 上表达的触发受体的相互作用有关。在此，我们报告了一个高通量筛选 (HTS) 平台，可用于识别 TREM2 和半乳糖凝集素-3 相互作用的抑制剂。我们利用这种 HTS 检测筛选了针对中枢神经系统 (CNS) 相关疾病优化的化合物的重点库。MG-257 从该筛选中被鉴定为小分子的第一个例子，它可以基于对半乳糖凝集素-3（TREM2 的内源性配体）的高亲和力减弱 TREM2 信号传导。值得注意的是，MG-257 降低了活化小胶质细胞中促炎细胞因子的水平，