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

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.