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First-in-Class Covalent Inhibitors of PFKFB3: Discovery and Characterization in PDAC Models

Alessandra Fiore1, Antonio Scarano2, Giulia Antonini3

  • 1Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biochemistry, University of Verona, 37134 Verona, Italy.

Journal of Medicinal Chemistry
|May 26, 2026
PubMed

Insights

Researchers developed a novel covalent inhibitor targeting PFKFB3, a key enzyme in pancreatic cancer metabolism. This PFKFB3 inhibitor shows promise for treating pancreatic ductal adenocarcinoma with reduced toxicity.

Area of Science:

  • Biochemistry
  • Oncology
  • Medicinal Chemistry

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by metabolic reprogramming.
  • Direct inhibition of glycolytic enzymes is often limited by toxicity.
  • Targeting 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) offers an indirect strategy for modulating glycolysis.

Purpose of the Study:

  • To develop and characterize a first-in-class covalent inhibitor of PFKFB3.
  • To explore the therapeutic potential of PFKFB3 inhibition in pancreatic cancer.
  • To investigate the druggability of a previously unexploited cysteine residue in PFKFB3.

Main Methods:

  • Synthesis of a novel covalent PFKFB3 inhibitor (compound 6).
  • Enzyme assays, site-directed mutagenesis, and mass spectrometry to confirm binding and selectivity.
  • In vitro assessment of cell viability and in vivo efficacy in zebrafish xenografts.

Main Results:

  • Compound 6 demonstrated covalent binding and kinetic selectivity for PFKFB3.
  • The inhibitor reduced viability in multiple PDAC cell lines and suppressed tumor growth in vivo.
  • Combination therapy with compound 6 and standard chemotherapeutics showed synergistic effects.

Conclusions:

  • The study validates the druggability of a novel cysteine target in PFKFB3.
  • This first-in-class covalent PFKFB3 inhibitor presents a potential therapeutic strategy for PDAC.
  • The findings pave the way for innovative PFKFB3 inhibitor mechanisms of action.

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