Drug Discovery
allowing glucose metabolites to enter subsidiary pathways including pentose phosphate, serine biosynthesis, hexcosamine and glycerol synthesis pathway which support cancer proliferation and survival. Another metabolic role for PKM2 is a pro- posed direct interaction and stabilisation of Hif1 which in turn acts to promote glycolytic metabo- lism, angiogenesis and cancer progression55. An alternative glycolytic route which bypasses PK in the conversion of PEP into Pyruvate has recently been identified88,116. This route uncouples ATP and Pyruvate generation and could provide biosynthetic intermediates without potential feedback inhibition of glycolysis from ATP accumulation (Figure 3). The key question around PKM2 is whether acti- vators or inhibitors or PKM2 kinase activity would be the best strategy and if PK-M2 would really be a cancer specific target. Recent publications have shown that progress is being made in designing tool compounds117,118 to test out the PKM2 hypothesis and it will be interesting to monitor the outcome of studies with these and other PKM2 modulation agents to see if a clear rationale and patient selection strategy can be defined for this complex metabolic target.
Isocitrate dehydrogenase (IDH1/2) Advances in large scale sequencing technologies has enabled more in-depth profiling of the genetics of multiple metabolism and oncogenic components in
Drug Discovery World Fall 2011
far larger sample sets (often more than 200 samples) and in multiple tumour types. Using these tech- niques it has been found that 60-90% of secondary gliomas (around 5% of primary gliomas)27,119 and 12-18% of acute myeloid leukaemias have muta- tions in the oxidative phosphorylation/TCA cycle components IDH1 or IDH226,120,121. For gliomas the common mutations are IDH1 Arg132 and IDH2 Arg140 and Arg172 whereas for glioma most muta- tions are in the IDH2 protein1,27,120. It is also worth noting that the vast majority of these muta- tions are heterozygous.
Mutations affecting the catalytic sites of IDH1 or 2 are thought to be functionally equivalent and were initially reported to negatively affect IDH catalytic activity by reducing isocitrate binding and the ability to convert isocitrate into alpha- ketoglutarate (-KG). However, recent mass-spec- troscopy data has discovered IDH mutations exhibit an altered catalytic activity and convert - KG (the product of wild type IDH proteins) to 2- hydorxyglutarate (Figure 4)120-122. This altered metabolite is found to be 100-fold increased in glioma or AML patients with IDH mutations sug- gesting it could act as a clinical biomarker120. Large scale analysis of DNA methylation in human gliomas provided a key insight into the role of this mutation in cancer. This study showed that nearly all IDH1 and IDH2 mutations were associated with a highly specific DNA methylation
Figure 4
Isocitrate dehydrogenase mutations and the TCA cycle. In the normal mitochondrial TCA cycle IDH2/3 enzymes convert isocitrate to - ketoglutarate (-KG) and IDH1 converts cytoplasmic isocitrate to -KG. However, mutant IDH1/2 enzymes (shown in red boxes) have a neomorphic enzyme capacity and convert -KG into 2- hdyroxyglutarate (2-HG). 2- HG is believed to inhibit -KG dependent processes including TET1/2 methyltransferase and the histone demethylase KDMa2 leading to epigenetic disregulation. 2HG may also act to stabilise HIF1. Abbreviations: CS – citrate synthase; ACO1/2 – Aconitase 1/2; IDH – isocitrate dehydrogenase; mIDH – mutant isocitrate dehydrogenase; OGDH – oxoglutarate (-ketoglutarate) dehydrogenase; SCS – succinyl- CoA synthetase; SDH – succinate dehydrogenase; FH – Fumarate hydratase; MDH2 – malate dehydrogenase 2; PDH – pyruvate dehydrogenase; GLS1 – glutaminase 1
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