Drug Discovery


Many potential drug targets within the metabol- ic field are currently being evaluated as potential therapeutics in all stages of the drug development progress from early development, through pre-clin- ical development and into clinical trials although as yet no agent targeting a core metabolic pathway has been approved for cancer6. Figure 1 summaries some of the core metabolic pathways and some of the agents in development looking to target differ- ent areas of cancer metabolism. In order to fully understand why there are so many agents and pathways under consideration in cancer metabo- lism it is important to investigate the main drivers for targeting cancer metabolism. The rest of this review will therefore consider why cancer metabo- lism could make an attractive area for therapeutic intervention and how our understanding of these pathways and advances in technology/knowledge is driving the hunt for new therapeutics.


Cancer metabolism and the Warburg Effect Dividing cells require ATP to maintain energy sta- tus, increased biosynthetic intermediates and maintenance of cellular redox status. In order to meet these needs carbohydrates, proteins, nucleotide and lipid alterations are required. Both


Drug Discovery World Fall 2011


cancer cells and rapidly proliferating normal cells require some of these adaptations for prolifera- tion, however cancer cells must implement these processes in very different and often harsh or stressful environments where nutrients supplies may be low and where redox balance, pH and oxygen levels may not be maintained. Cancer cells have found ways to adapt to these dynamic situa- tions and regulate their metabolic status in order to survive, grow and even prosper.


The links between cancer and altered metabo- lism is not a new phenomenon. Otto Warburg, a Nobel prize-winning scientist (for the discovery of cytochrome oxidase) noted more than 80 years ago that in tumour tissue slices ATP is generated from glucose via aerobic glycolysis which is an oxygen independent process rather than by oxygen dependent oxidative phosphorylation even when oxygen is present7,8. This switch in ATP generation which has been termed the Warburg Effect is ini- tially paradoxical as while ATP generation is more rapid via glycolytic pathways, far less ATP is gen- erated (2 molecules ATP/molecule glucose) than via oxidative phosphorylation (up to 36 molecules ATP/molecule glucose).


In more recent times this switch has been attrib- uted to the ability of glycolytic pathways to supply


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Figure 1 Targeting tumour metabolism. Core metabolic pathways and enzymes against which inhibitors (shown in red) have been reported. Key enzymes are shown in green boxes and key biosynthetic endpoints listed in purple. Abbreviations: GLUT – Glucose transporter; HK2 – Hexokinase-2; PFK1 – Phosphofructokinase 1; PFKFB3 – 6-phosphofructo-2- kinase/fructose-2,6- biphosphatase 3; PK-M2 – pyruvate kinase-M2; LDHa – lactate dehydrogenase-A; MCT1/4 – Monocarboxylate transporter’s 1/4; AMPK – AMP activated protein kinase; G6PD – glucose-6-phosphate dehydrogenase; TKT – transketolase; TKTL1 – transketolase like -1; ASCT2 – solute carrier family 1, member 5 [SLC1A5]; GLS1 – Glutaminase 1; ME – malic enzyme; FH – fumarate hydratase; SDH – succinate dehydrogenase; PDH – pyruvate dehydrogenase; PDK1 – pyruvate dehydrogenase kinase 1; ACLY – ATP citrate lyase; ACACA – acetyl-CoA carboxylase alpha; FASN – fatty acid synthase; CA9/12 – carbonic anhydrase 9/12; NHE1- Na+-H+ exchanger [SLC9A1]

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