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。
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.