Identification of small molecule inhibitors of pyruvate kinase M2

Dana-Farber Cancer Institute, Boston, MA 02115, United States.
Biochemical pharmacology (Impact Factor: 5.01). 12/2009; 79(8):1118-24. DOI: 10.1016/j.bcp.2009.12.003
Source: PubMed


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.

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Available from: Heather R Christofk, Jan 07, 2014
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    • "More recently, glutamine has been identified as a critical nutrient for cancer cells to replenish TCA cycle metabolites for the biosynthesis of lipids and mitochondrial ATP production (DeBerardinis et al., 2007; Hensley et al., 2013), complementing the altered state of glucose metabolism. Therapeutic strategies harnessing altered metabolic properties of cancer cells are currently focused on developing specific inhibitors against key metabolic enzymes, such as glutaminase (Le et al., 2012; Robinson et al., 2007; Thangavelu et al., 2012) and PKM2 (Christofk et al., 2008; Vander Heiden et al., 2010). In principle , the activation or inhibition of transcriptional master regulators of metabolic processes presents another promising strategy to target cancer metabolism and may achieve a more selective response. "
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    • "A series of PKM2 activators (1-(sulfonyl)-5-(arylsulfonyl)indoline) were also reported very recently [86]. In contrast to these, potent small molecule PKM2 inhibitors which may in part induce cell death by inhibiting PKM2 activity have also been developed [87]. Furthermore, the pyruvate kinase activity of PKM2 can be inhibited by association with several distinct proteins. "
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