PMID:20005212

Citation	Vander Heiden, MG, Christofk, HR, Schuman, E, Subtelny, AO, Sharfi, H, Harlow, EE, Xian, J and Cantley, LC (2010) Identification of small molecule inhibitors of pyruvate kinase M2. Biochem. Pharmacol. 79:1118-24
Abstract	A common feature of tumors arising from diverse tissue types is a reliance on aerobic glycolysis for glucose metabolism. This metabolic difference between cancer cells and normal cells could be exploited for therapeutic benefit in patients. Cancer cells universally express the M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2), and previous work has demonstrated that PKM2 expression is necessary for aerobic glycolysis and cell proliferation in vivo. Because most normal tissues express an isoform of pyruvate kinase other than PKM2, selective targeting of PKM2 provides an opportunity to target cell metabolism for cancer therapy. PKM2 has an identical catalytic site as the related M1 splice variant (PKM1). However, isoform selective inhibition is possible as PKM2 contains a unique region for allosteric regulation. We have screened a library of greater than 1,00,000 small molecules to identify such inhibitors. The inhibitors identified for PKM2 fell primarily into three distinct structural classes. The most potent PKM2 inhibitor resulted in decreased glycolysis and increased cell death following loss of growth factor signaling. At least part of this effect was due to on-target PKM2 inhibition as less cell death was observed in cells engineered to express PKM1. These data suggest that isoform selective inhibition of PKM2 with small molecules is feasible and support the hypothesis that inhibition of glucose metabolism in cancer cells is a viable strategy to treat human malignancy.
Links	PubMed PMC2823991 Online version:10.1016/j.bcp.2009.12.003
Keywords	Cell Line; Enzyme Inhibitors/pharmacology; Fructosediphosphates/metabolism; Glucose/metabolism; Glycolysis/drug effects; High-Throughput Screening Assays; Humans; Isoenzymes/antagonists & inhibitors; L-Lactate Dehydrogenase/metabolism; Pyruvate Kinase/antagonists & inhibitors
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:KPYM		GO:0004743: pyruvate kinase activity	ECO:0000314:		F		Figure 2 kinetic characterization of enzyme activity	complete CACAO 6188
HUMAN:KPYM	enables	GO:0004743: pyruvate kinase activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete

References

See Help:References for how to manage references in GONUTS.