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
  • 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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