Development of Novel Irreversible Pyruvate Kinase M2 Inhibitors

As
cancer cells undergo metabolic reprogramming in the course of
tumorigenesis, targeting energy metabolism represents a promising
strategy in cancer therapy. Among various metabolic enzymes examined,
pyruvate kinase M2 type (PKM2) has received much attention in light
of its multifaceted function in promoting tumor growth and progression.
In this study, we reported the development of a novel irreversible
inhibitor of PKM2, compound 1, that exhibits a differential
tumor-suppressive effect among an array of cancer cell lines. We further
used a clickable activity-based protein profiling (ABPP) probe and
SILAC coupled with LC-MS/MS to identify the Cys-317 and Cys-326 residues
of PKM2 as the covalent binding sites. Equally important, compound 1 at 10 mg/kg was effective in suppressing xenograft tumor
growth in nude mice without causing acute toxicity by targeting both
metabolic and oncogenic functions. Together, these data suggest its
translational potential to foster new strategies for cancer therapy.