Abstract：
The STING (stimulator of interferon genes) pathway is one of the pathways that regulate innate immunity, and the extracellular hydrolytic enzyme ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) has been identified as its dominant negative regulator. Since activation of the innate immune system is a promising strategy for the treatment of various infectious diseases and cancers, ENPP1 inhibitors have attracted great attention as candidate drugs. We have previously identified small-molecule ENPP1 inhibitors having a [1,2,4]triazolo[1,5-a]pyrimidine scaffold by means of chemical screening using a fluorescence probe, TG-mAMP. In this study, we evaluated the structure-activity relationships of the hit and lead compounds in detail, and succeeded in developing compounds that strongly and selectively inhibit ENPP1 not only in vitro, but also in cellular systems.
摘要：
STING（干扰素基因刺激因子）途径是调节先天免疫的途径之一，胞外水解酶外核苷酸焦磷酸酶/磷酸二酯酶1（ENPP1）已被确定为其主要的负调节因子。由于激活先天免疫系统是治疗各种传染病和癌症的有前途的策略，ENPP1抑制剂作为候选药物引起了极大的关注。我们先前已经通过使用荧光探针的化学筛选鉴定了具有[1,2,4]三唑并[1,5-a]嘧啶支架的小分子ENPP1抑制剂，TG-mAMP。在这项研究中,我们详细评估了命中和先导化合物的结构-活性关系，并成功开发出不仅在体外强烈且选择性地抑制ENPP1的化合物，而且在蜂窝系统中。
