Podophyllotoxin derivative hits PGK1 to curb glycolysis in liver cancer models
- Chemical proteomics combined with phenotypic profiling identified phosphoglycerate kinase 1 as the target of a new podophyllotoxin derivative, αFOD; modelling against an in-house crystal structure places it in the 3-phosphoglycerate pocket, with modest binding affinity.
- The compound blocked PGK1 enzyme activity and glycolytic flux in HepG2 cells, and favoured tumour over non-malignant cells in culture.
- It was active in HCC cell lines and patient-derived organoids, and in a HepG2 xenograft it curbed tumour growth more than etoposide, with less systemic toxicity than oxaliplatin.
💡 Points Based on the abstract
PGK1 is a plausible but caveat-heavy target: glycolysis is broadly essential, so the 'tumour-selective' claim needs real therapeutic-window data, not a HepG2 xenograft. Modest docking affinity in the 3-PG pocket plus a podophyllotoxin scaffold makes me suspect polypharmacology (tubulin, topo II). I'd want a PGK1 knockdown rescue and exposure data before funding more.