Researchers at sanofi-aventis have developed compounds that release the brakes on p53, a protein often called the ‘guardian of the genome’ because of its importance in repairing damaged DNA. The compounds shrank tumours in mice grafted with human cancer cells.

p53 has been heralded as a key to beating cancer. Over half of all human tumours carry mutations in the protein, and activating p53 in mice wipes out tumours.

sanofi’s compounds, designed in collaboration with academic chemists, block the interaction between p53 and a protein, called MDM2, that inhibits it. Other molecules that inhibit this interaction block tumour growth, but fail to shrink tumours in animal models.

It is early days yet for sanofi’s drugs: so far they have only been tested in cell cultures and mice, and researchers will have to conduct additional animal studies to detect possible side effects and determine optimal doses before the drug could be tested in the clinic.

But the results, presented on 4 April as a poster at the annual meeting of the American Association for Cancer Research in Orlando, Florida, represent an achievement on several fronts. Cancer researchers have searched for decades to find a viable drug that can stimulate p53. And it is also particularly difficult to design drugs that specifically block the interaction between two proteins.

That difficulty has several causes, explains sanofi’s Carlos Garcia-Echeverria, global head of oncology chemistry and pharmacology. Companies often search for drugs by screening large libraries of compounds. But those libraries reflect the history of the company, says Garcia-Echeverria, and were originally derived with other targets in mind – proteins called kinases, for example, or ion channels, which are common drug targets. Such libraries may not have the unique molecules needed to interfere with protein-protein interactions.

What’s more, the interactions between proteins often span a surface area that is larger than many small molecule drugs. Generally speaking, the bigger a molecule gets, the more difficult it may be to synthesize and the more troublesome it may be to optimize.

But chemist Shaomeng Wang at the University of Michigan was undaunted. Wang tackled the p53-MDM2 interaction by first solving the molecular structure of the two proteins in complex, and identifying the key regions responsible for their interaction. He then used modeling to determine what compounds would block that interaction.

Wang also took a step further than many academics are willing to go, treading into the murky world of medicinal chemistry to increase the potency of his compounds and enhance their ability to enter cells.

sanofi’s scientists took note and built upon Wang’s work. The result: two spirooxindole compounds with potent anti-tumour activity in mice. In one assay, the sanofi team planned to measure tumour size in mice grafted with human osteosarcoma cells. They decided to take the measurements once every week, says Laurent Debussche, director of cancer biology drug discovery and preclinical development at sanofi. But after one week, he says, the measurements were completed. The tumours were gone, with no obvious signs of unwanted side effects in the mice. Expression of genes induced by p53 also increased with increasing doses of the drugs.

sanofi is exploring which cancers are most likely to respond to such a drug, but one likely candidate is liposarcoma, a disease that is highly resistant to chemotherapy. Most liposarcomas contain extra copies of the MDM2 gene.