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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    ABSTRACT: The nuclear receptor peroxisome-proliferation-activated receptor gamma (PPARγ), a transcriptional master regulator of glucose and lipid metabolism, inhibits the growth of several common cancers, including lung cancer. In this study, we show that the mechanism by which activation of PPARγ inhibits proliferation of lung cancer cells is based on metabolic changes. We found that treatment with the PPARγ agonist pioglitazone triggers a metabolic switch that inhibits pyruvate oxidation and reduces glutathione levels. These PPARγ-induced metabolic changes result in a marked increase of reactive oxygen species (ROS) levels that lead to rapid hypophosphorylation of retinoblastoma protein (RB) and cell-cycle arrest. The antiproliferative effect of PPARγ activation can be prevented by suppressing pyruvate dehydrogenase kinase 4 (PDK4) or β-oxidation of fatty acids in vitro and in vivo. Our proposed mechanism also suggests that metabolic changes can rapidly and directly inhibit cell-cycle progression of cancer cells by altering ROS levels.
    Cell Metabolism 09/2014; 20(4). DOI:10.1016/j.cmet.2014.08.003 · 17.57 Impact Factor
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    • "This tissue proteomic analysis and validation indicated that PKM2 and cofilin-1 could be potential therapeutic targets for pulmonary adenocarcinoma. It should be noted that small molecule inhibitors of PKM2 were identified and shown to inhibit cancer cell glycolysis and increase cancer cell death following the loss of growth factor signaling,127 which was consistent with the proteomics-driven conclusion. Cofilin-1 has long been associated with increased tumor metastasis due to its role in regulating cytoskeleton dynamics,128 and the inhibition of cofilin-1 by small molecule inhibitors has been demonstrated to enhance actin depolymerization.129 "
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    ABSTRACT: Proteomic approaches are continuing to make headways in cancer research by helping to elucidate complex signaling networks that underlie tumorigenesis and disease progression. This review describes recent advances made in the proteomic discovery of drug targets for therapeutic development. A variety of technical and methodological advances are overviewed with a critical assessment of challenges and potentials. A number of potential drug targets, such as baculoviral inhibitor of apoptosis protein repeat-containing protein 6, macrophage inhibitory cytokine 1, phosphoglycerate mutase 1, prohibitin 1, fascin, and pyruvate kinase isozyme 2 were identified in the proteomic analysis of drug-resistant cancer cells, drug action, and differential disease state tissues. Future directions for proteomics-based target identification and validation to be more translation efficient are also discussed.
    Drug Design, Development and Therapy 10/2013; 7:1259-1271. DOI:10.2147/DDDT.S52216 · 3.03 Impact Factor
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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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    ABSTRACT: Aerobic glycolysis is the dominant metabolic pathway utilized by cancer cells, owing to its ability to divert glucose metabolites from ATP production towards the synthesis of cellular building blocks (nucleotides, amino acids, and lipids) to meet the demands of proliferation. The M2 isoform of pyruvate kinase (PKM2) catalyzes the final and also a rate-limiting reaction in the glycolytic pathway. In the PK family, PKM2 is subjected to a complex regulation by both oncogenes and tumour suppressors, which allows for a fine-tone regulation of PKM2 activity. The less active form of PKM2 drives glucose through the route of aerobic glycolysis, while active PKM2 directs glucose towards oxidative metabolism. Additionally, PKM2 possesses protein tyrosine kinase activity and plays a role in modulating gene expression and thereby contributing to tumorigenesis. We will discuss our current understanding of PKM2's regulation and its many contributions to tumorigenesis.
    International Journal of Cell Biology 02/2013; 2013:242513. DOI:10.1155/2013/242513
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