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 <b>6e</b>, a potent and selective PGK1 inhibitor featuring a novel scaffold. Notably, <b>6e</b> exhibits remarkable selectivity across 210 protein kinases and favorable pharmacokinetic profiles in rodents. In vitro, <b>6e</b> inhibits PGK1-mediated glycolytic metabolism and reduces glucose consumption/lactate production. Mechanistic studies revealed that <b>6e</b> 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, <b>6e</b> 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.