S100 蛋白家族充当受 Ca2 结合调节的蛋白质-蛋白质相互作用接头。各种 S100 复合物的形成在从钙稳态到细胞信号传导的细胞功能中发挥着核心作用，并与细胞生长、迁移和肿瘤发生有关。我们基于已知的 S100 蛋白质-蛋白质相互作用建立了一套用于小分子筛选的生化和细胞测定法。在 25 种人类 S100 蛋白中，我们将注意力集中在 S100A4 上，因为它通过与非肌肉肌球蛋白 II (NMII) 相互作用在癌症进展和转移中发挥着明确的作用。我们鉴定了这种相互作用的几种有效且选择性的抑制剂，并通过质谱和晶体结构证实了结合的共价性质。图5b显示了细胞中的靶向活性和对癌细胞迁移的抑制。已鉴定的 S100A4 抑制剂可以作为发现通过新颖作用模式发挥作用的新抗癌药物的基础。

The S100 protein family functions as protein-protein interaction adaptors regulated by Ca2+ binding. Formation of various S100 complexes plays a central role in cell functions, from calcium homeostasis to cell signaling, and is implicated in cell growth, migration, and tumorigenesis. We established a suite of biochemical and cellular assays for small molecule screening based on known S100 protein-protein interactions. From 25 human S100 proteins, we focused our attention on S100A4 because of its well-established role in cancer progression and metastasizes by interacting with nonmuscle myosin II (NMII). We identified several potent and selective inhibitors of this interaction and established the covalent nature of binding, confirmed by mass spectrometry and crystal structures. 5b showed on-target activity in cells and inhibition of cancer cell migration. The identified S100A4 inhibitors can serve as a basis for the discovery of new cancer drugs operating via a novel mode of action.