Human Macrophage Migration Inhibitory Factor (MIF) is a trimeric cytokine implicated in a number of inflammatory and autoimmune diseases and cancer. We previously reported that the dye p425 (Chicago Sky Blue), which bound MIF at the interface of two MIF trimers covering the tautomerase and allosteric pockets, revealed a unique strategy to block MIF’s pro-inflammatory activities. Structural liabilities, including the large size, precluded p425 as a medicinal chemistry lead for drug development. We report here a rational design strategy linking only the fragment of p425 that binds over the tautomerase pocket to the core of ibudilast, a known MIF allosteric site-specific inhibitor. The chimeric compound, termed L2-4048, was shown by X-ray crystallography to bind at the allosteric and tautomerase sites as anticipated. L2-4048 retained target binding and blocked MIF’s tautomerase CD74 receptor binding, and pro-inflammatory activities. Our studies lay the foundation for the design and synthesis of smaller and more drug-like compounds that retain the MIF inhibitory properties of this chimera.

中文翻译：

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两种变构结合剂的嵌合体对巨噬细胞迁移抑制因子的抑制作用

人类巨噬细胞迁移抑制因子 (MIF) 是一种三聚体细胞因子，与多种炎症和自身免疫性疾病以及癌症有关。我们之前报道过染料 p425（芝加哥天蓝）在两个 MIF 三聚体的界面处结合 MIF，覆盖互变异构酶和变构袋，揭示了一种独特的策略来阻止 MIF 的促炎活动。结构性缺陷，包括大尺寸，排除了 p425 作为药物开发的药物化学先导。我们在此报告了一种合理的设计策略，仅将通过互变异构酶袋结合的 p425 片段与异丁司特（一种已知的 MIF 变构位点特异性抑制剂）的核心联系起来。X 射线晶体学显示，称为 L2-4048 的嵌合化合物如预期在变构和互变异构酶位点结合。L2-4048 保留了靶标结合并阻断了 MIF 的互变异构酶 CD74 受体结合和促炎活性。我们的研究为设计和合成更小、更像药物的化合物奠定了基础，这些化合物保留了这种嵌合体的 MIF 抑制特性。