Discovery of a Novel Potent and Orally Efficacious PGK1 Inhibitor C67-47 for the Treatment of Human Pancreatic Cancer

  • J Med Chem. 2026 Jun 11;69(11):12955-12972. doi: 10.1021/acs.jmedchem.5c03549.
Lihua Liu  1 ,  Xiaoming Jiang  1 ,  Hong Zhao  2 ,  Hongli Yang  1 ,  Hao Yang  1 ,  Dong Guo  2 ,  Shudi Luo  1 ,  Qingqing Yang  2 ,  Suyao Li  2 ,  Lihui Wu  2 ,  Dou Nie  2 ,  Zhimin Lu  2  3  4  5 ,  Xin Han  1  4  5  6
Affiliations
  • 1. Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China.
  • 2. Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310029, China.
  • 3. Institute of Fundamental and Transdisciplinary Research, Zhejiang University, Hangzhou, Zhejiang 310029, China.
  • 4. Cancer Center of Zhejiang University, Hangzhou 310029, China.
  • 5. The Center for Translational Research, the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University, Hangzhou, Zhejiang 310029, China.
  • 6. Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang Province 310009, China.
PMID: 42214065 DOI: 10.1021/acs.jmedchem.5c03549
Abstract

Phosphoglycerate kinase 1 (PGK1), the first ATP-generating enzyme in glycolysis, is frequently overexpressed in a wide range of human malignancies. Beyond its canonical glycolytic function, PGK1 also functions as a protein kinase playing a critical role in tumorigenesis and Cancer progression. Here, we report the identification of a novel and highly potent PGK1 inhibitor through structure-based high-throughput virtual screening, exemplified by compound 42 (C67-47). C67-47 binds strongly to PGK1 with a dissociation constant (Kd) of 63 nM and exhibits potent antiproliferative effects in pancreatic Cancer cells. In preclinical studies, C67-47 demonstrated excellent oral pharmacokinetics in both mouse and rat models. Strikingly, a single oral dose of C67-47 resulted in up to 80% tumor growth inhibition in pancreatic Cancer xenograft models with no observable toxicity. These findings establish C67-47 as a promising lead compound for the development of orally administered, PGK1-targeted therapies for pancreatic Cancer.

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