Tackling Pancreatic Ductal Adenocarcinoma with an Innovative Covalent Targeting of Glycolysis

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis. Metabolic reprogramming drives its malignancy, making cancer metabolism an attractive therapeutic target. However, anti-glycolytic therapies face clinical limitations due to toxicity. Inhibition of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB), particularly the PFKFB3 isoform, may offer a safer therapeutic window.[1] Herein, we report the first covalent PFKFB3 inhibitor featuring moderately reactive, drug-like warheads targeting a previously unexplored cysteine within the active site. Biochemical assays confirmed irreversible enzyme inhibition and covalent binding. Our lead compound selectively reduced viability across multiple PDAC cell lines and, in vivo, effectively suppressed tumor growth in zebrafish xenograft models, highlighting its potent and specific antitumor activity. Moreover, combination of compound 6 with standard chemotherapeutics (Gemcitabine, FOLFIRINOX) enhanced efficacy, revealing synergistic effects. This work introduces a novel covalent PFKFB3 inhibitor and supports anti-glycolytic therapy as a promising strategy for PDAC treatment.