It has been estimated that greater than one in three people are likely to develop cancer at some point in their life. As a result cancer is the second most common cause of death in Australia and New Zealand, after cardiovascular disease. Cancer cells are believed to develop due to the accumulation of mutations within their genes, resulting in these cells growing and dividing in an uncontrolled manner. Cancer cells require a large amount of energy, in the form of glucose, to sustain their rapid growth. Most cancerous cells grow under hypoxic conditions and have differences in their metabolism of glucose, known as the Warburg effect, to avoid apoptosis.
Poly (ADP-ribose) polymerase, member 14 (PARP14) belongs to a family of intracellular proteins that generate ADP-ribose post transitional adducts.1 It has recently been demonstrated that PARP14 promotes the Warburg effect in hepatocellular carcinoma cells and that PARP14 levels are increased in cancer cells when compared to normal cells.3 In recently reported research when the PARP14 protein was blocked (using a shRNA knockdown model) the cancer cells had a significantly slower rate of growth while the normal cells growth rate was not affected.2
Our research explores the structure, nature and function of PARP14 using computational chemistry techniques. By targeting TYR1620, located on the edge of the catalytic binding site, we may be able to selectively target PARP14 over the other PARP enzymes.3 We have designed a novel library of PARP14 inhibitors that have strong binding interactions with TYR1620. A potent inhibitor that is selective for PARP14 could potentially be able to “starve cancer to death”.