Macrophage migration inhibitory factor (MIF) is an essential signaling cytokine with a key role in the immune system. Binding of MIF to its molecular targets such as, among others, the cluster of differentiation 74 (CD74) receptor plays a key role in inflammatory diseases and cancer. Therefore, the identification of MIF binding compounds gained importance in drug discovery. In this study, we aimed to discover novel MIF binding compounds by screening of a focused compound collection for inhibition of its tautomerase enzyme activity. Inspired by the known chromen-4-one inhibitor Orita-13, a focused collection of compounds with a chromene scaffold was screened for MIF binding. The library was synthesized using versatile cyanoacetamide chemistry to provide diversely substituted chromenes. The screening provided inhibitors with IC₅₀’s in the low micromolar range. Kinetic evaluation suggested that the inhibitors were reversible and did not bind in the binding pocket of the substrate. Thus, we discovered novel inhibitors of the MIF tautomerase activity, which may ultimately support the development of novel therapeutic agents against diseases in which MIF is involved.

巨噬细胞迁移抑制因子 (MIF) 是一种重要的信号细胞因子，在免疫系统中起关键作用。MIF 与其分子靶标的结合，例如分化簇 74 (CD74) 受体在炎症性疾病和癌症中起关键作用。因此，MIF 结合化合物的鉴定在药物发现中具有重要意义。在这项研究中，我们旨在通过筛选抑制其互变异构酶活性的集中化合物集合来发现新的 MIF 结合化合物。受已知的 chromen-4-one 抑制剂 Orita-13 的启发，针对 MIF 结合筛选了一组具有 chromen 支架的化合物。该文库是使用通用的氰基乙酰胺化学合成的，以提供多种取代的色烯。筛选提供了具有 IC 的抑制剂₅₀在低微摩尔范围内。动力学评估表明抑制剂是可逆的并且不结合在底物的结合袋中。因此，我们发现了 MIF 互变异构酶活性的新型抑制剂，这可能最终支持开发针对 MIF 相关疾病的新型治疗剂。