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.