Researchers from Swiss pharmaceutical company Roche have discovered a class of chemical compound that could form the basis of a new approach to tackling cancer. The new compounds prevent the deactivation of a cellular protein that is an important natural bodily defence against cancerous tumours. 

In response to genotoxic stress, the tumour suppresser protein p53 can stop cancerous cells from reproducing and force them to commit suicide (apoptosis). Under normal conditions, the expression of p53 is tightly controlled by another protein known as MDM2, which binds to p53 to block its activity and also promotes its degradation. In cancer cells, however, MDM2 is often over-expressed and prevents p53 from attacking the tumour.

MDM2 possesses a relatively deep hydrophobic pocket, in which it binds to p53. The Roche researchers wondered whether they could identify a compound that would fill the pocket and thereby block the interaction between MDM2 and p53.

By screening a diverse library of synthetic chemicals, they discovered a class of cis-imidazoline analogues, which they called Nutlins, that could displace p53 from its complex with MDM2.

According to the researchers, tests of the Nutlins on cancer cells showed that they prevented MDM2 from deactivating p53, which accumulated in the cells and stopped them from proliferating. The research team carried out further tests on established tumours in mice and claims that the Nutlins inhibited cancer growth by as much as 90 per cent. 

JE