Drug Discovery
cell’s high demand for these metabolites. For glu- cose, this initial step is conversion to glucose-6- phosphate by the hexokinase’s of which hexoki- nase 2 appears to predominant in many cancers71 and has shown to be regulated by both AKT58 and mutant p5372. siRNA studies or use of non- hydrolysable glucose mimics which have been shown to inhibit Hexokinase-2 activity, suggest that modulating Hexokinase-2 activity could be of therapeutic benefit in cancer73-75. Two of these
potential hexokinase inhibitors; 2-doexyglucose76- 78 and 3-bromopyruvate71,74 have shown promis- ing anti-cancer activity in multiple pre-clinical models but as yet data from clinical trials has not supported their use as clinical anti-cancer agents. For glutamine the first step is conversion of glu- tamine to glutamate by glutaminase proteins (GLS1/2)79. GLS1 expression has been shown to be increased in several tumour types and to be under indirect control from Myc via myc-depend- ent regulation of miR23a/b levels31,80. Studies using siRNA technology81 or potential inhibitors of GLS1 (DON82, 96883) have suggested that inhi- bition of this target could be of benefit in gluta- mine dependent tumour cells.
The next phase of metabolite processing involves the conversion of these metabolites into a series of
Figure 2
Key phases of cancer cell metabolism. Dashed boxes
represent the four key phases of metabolism and illustrate
the key proteins, intermediates or biosynthetic products within each phase.
Abbreviations: GLUT –
Glucose transporter; ASCT2 – solute carrier family 1; member 5 [SLC1A5]; HK – Hexokinase; GLS – Glutaminase; MCT –
Monocarboxylate transporter
intermediates through metabolic cascades. This process is not a liner and intermediates can be fur- ther processed through branched pathways (ie tri- carboxylic acid cycle, pentose phosphate pathway or serine biosynthesis pathway) to yield additional products (see Figure 1). The net result of all the pro- cessing pathways of core metabolism is; the genera- tion of biosynthetic intermediates for the manufac- ture of lipids, proteins, nucleotides and complexes sugars, the generation of energy in the form of ATP and the generation of key co-factors, ie glutathione, NADH and NADPH, which are essential for the functionality of many protein and have key roles in protecting the cell from oxidative stress. Multiple proteins on these pathways have been shown to be over expressed in cancer, dependent on oncogenic control or in inhibition studies (RNAi or tool com- pounds) been shown to be involved in cell prolifer- ation and/or survival mechanisms. Proteins which are of potential interest as possible therapeutic tar- gets include the glycolytic enzymes84 (eg Hexokinase-271, Phosphoglycerate kinase-185,86, Phosphoglycerate mutase87,88 and Pyruvate kinase- m228,89-91); the pentose phosphate proteins (eg Glucose-6-phosphate dehydrogenase92-94, transal- dolase95 and transketolase96-98) and lipid synthe- sis/fatty acid metabolism targets (eg ATP citrate
68
Drug Discovery World Fall 2011
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