Discovery of Novel Purine Derivatives as Potent and Orally Bioavailable PGK1 Inhibitors for the Treatment of Inflammatory Bowel Disease

Phosphoglycerate kinase 1 (PGK1) has garnered increasing attention as a potential therapeutic target for inflammatory bowel disease (IBD). Current PGK1 inhibitors face limitations in potency and pharmacokinetics, necessitating improved agents. Herein, we report the structure-guided rational optimization of purine derivatives, leading to the identification of 6e, a potent and selective PGK1 inhibitor featuring a novel scaffold. Notably, 6e exhibits remarkable selectivity across 210 protein kinases and favorable pharmacokinetic profiles in rodents. In vitro, 6e inhibits PGK1-mediated glycolytic metabolism and reduces glucose consumption/lactate production. Mechanistic studies revealed that 6e enhances Nrf2 accumulation and HO-1 expression and suppresses the transcription and protein levels of the inflammatory cytokines IL-1β and IL-6. In vivo, 6e effectively ameliorates colon shortening and histopathology in dextran sulfate sodium (DSS)-induced experimental colitis in mice. Collectively, this study provides a therapeutically promising lead compound for targeting PGK1 in IBD while also serving as a valuable tool for investigating PGK1 mechanisms in diverse diseases.磷酸甘油酸激酶1（PGK1）作为炎症性肠病（IBD）的潜在治疗靶点，正日益受到广泛关注。当前的PGK1抑制剂在效力与药代动力学方面存在局限，亟需开发更优的靶向制剂。本研究通过基于结构的理性优化策略对嘌呤衍生物进行改造，成功筛选得到化合物6e——一种具有全新骨架的强效且高选择性PGK1抑制剂。值得注意的是，6e在210种蛋白激酶中展现出优异的选择性，且在啮齿类动物体内具备良好的药代动力学特性。体外实验中，6e可抑制PGK1介导的糖酵解代谢过程，并降低葡萄糖消耗与乳酸生成水平。机制研究表明，6e可促进核因子E2相关因子2（Nrf2）的积累与血红素氧合酶1（HO-1）的表达，同时抑制炎症细胞因子白细胞介素1β（IL-1β）与白细胞介素6（IL-6）的转录及蛋白表达水平。体内实验中，6e可有效改善葡聚糖硫酸钠（DSS）诱导的小鼠实验性结肠炎的结肠缩短及组织病理学异常。综上，本研究不仅为靶向PGK1治疗IBD提供了极具开发前景的先导化合物，同时也为探究PGK1在多种疾病中的作用机制提供了极具价值的研究工具。