New insights into a key cancer pathway – known as p53 – have been uncovered by scientists at Roche. In a paper published in the February 6 issue of Science and Sciencexpress, for the first time, researchers have identified a small molecule that activates the p53 pathway by preventing the binding between p53 and its inhibitor, MDM2. It was believed that it would not be possible to create a potent small molecule p53-MDM2 binding inhibitor. The new research shows that this is now possible.
The tumour suppressor p53 is a potent transcription factor controlling a major pathway, which protects cells from becoming malignant. This makes it the most frequently inactivated protein in human cancer and therefore an important pathway to target for cancer therapy. Approximately 50 per cent of all human tumours have dysfunctional p53. It is believed that in the rest of the human malignancies the tumour suppressor is disabled by other mechanisms. One such mechanism is the overproduction of its natural inhibitor MDM2. “By inhibiting MDM2 we can stabilize and activate p53, which leads to growth arrest and apoptosis (cell death) in tumour cells,” noted Lyubomir Vassilev, research leader at Roche, and lead author on the paper. “Therefore, this new research may offer a novel strategy for cancer therapy and allow us to develop a small-molecule drug, which could be administered orally.”
Protein-protein interactions have historically posed a challenge in drug development. To identify the small molecule, Roche scientists screened a diverse library of chemicals via high throughput screening and identified a class of compounds, termed Nutlins, which inhibit tumour growth in mice by 90 percent, without producing harmful side effects. “Although MDM2 antagonists are likely to be most effective against those tumours that have abnormally high levels of MDM2, many of the 50 per cent of all patients with cancers harbouring wild-type p53 may also benefit from p53-activating therapy,” added Dr Vassilev.
“While many more studies are needed to assess the full therapeutic potential of Nutlins, this research has provided us with valuable tools for the discovery process, as well as increased our knowledge and understanding of the p53 pathway in many ways,” stated David Heimbrook, vice president, Nutley Oncology Research at Roche.