2. Academic Validation
  3. Discovery of Novel Purine Derivatives as Potent and Orally Bioavailable PGK1 Inhibitors for the Treatment of Inflammatory Bowel Disease

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

  • J Med Chem. 2025 Oct 23;68(20):21394-21411. doi: 10.1021/acs.jmedchem.5c01334.
Zhi Huang 1,  Juan Ge 1 2,  Yongfei Chen 1 3,  Fengming Zou 1 3,  Qingwang Liu 1 3,  Beilei Wang 1 3,  Yangguo Zhou 1 2,  Chao Wu 1 2,  Wenchao Wang 1 2 3 4,  Aoli Wang 1 3,  Jing Liu 1 2 3 4,  Qingsong Liu 1 2 3 4
Affiliations

Affiliations

  • 1 Hefei Cancer Hospital of CAS, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
  • 2 University of Science and Technology of China, Hefei, Anhui 230026, P. R. China.
  • 3 Precision Cancer Medicine Engineering Research Center of Anhui Province, Hefei, Anhui 230088, P. R. China.
  • 4 Primary Cell Engineering Joint Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China.
PMID: 41077732 DOI: 10.1021/acs.jmedchem.5c01334
Abstract

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.

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