Roche discovery could lead to new cancer drug class
that interferes with the binding of p53 - a protein that blocks the
development of cancer - to its natural inhibitor. The discovery
could open the door to novel, orally available drugs.
p53 prevents the development of cancer in cells by exerting tight control over cell replication. This control mechanism is deactivated in about 50 per cent of all human tumours - usually because the p53 protein itself is dysfunctional - so this pathway has been dissected by researchers for years, in the hope of finding an effective drug that will work in a broad range of cancer patients.
It is also known that p53 is inhibited by another molecule, called MDM2, and one research track has concentrated on blocking the binding of this factor to restore p53 function.
In a paper published in the 6 February issue of Science, scientists at Roche's research facilities in Nutley in the US describe how they identified the p53-MDM2 blockers - christened 'Nutlins' after Nutley inhibitors - by screening a diverse library of chemicals via HTS. They subsequently identified a class of compounds which inhibit tumour growth in mice by 90 per cent, without producing harmful side effects.
Lyubomir Vassilev, a research leader at Roche and the lead author on the paper, said that overall, 7 per cent of cancers are characterised by an overexpression of MDM2, although it is more common in certain types of malignancy such as sarcomas, with an incidence of 20-30 per cent.
"By inhibiting MDM2 we can stabilise and activate p53, which leads to growth arrest and apoptosis (cell death) in tumour cells," said Vassilev.
But such an approach may not be limited to MDM2-overexpressing cancers, he pointed out. Many of the 50 per cent of all patients with cancers harbouring 'wild-type' (functional) p53 may also benefit from the tumour-suppressing effect of p53-activating therapy, he suggested.
The programme is still in its infancy, and Vassilev would not be drawn on a timeframe for the first MDM2-targeting compounds from Roche entering clinical trials.
Many big pharmaceutical companies have started programmes looking at small molecule inhibitors of MDM2, but many of these have been terminated, despite the promise of the approach.
One team which is still working on the area is based at the University of Newcastle-upon-Tyne in the UK. The group recently signed an agreement with UK medicinal chemistry specialist De Novo Pharmaceuticals to improve the profile of some of its lead candidates.
Meanwhile, US antisense specialist Hybridon has taken a different approach to the target with the development of an antisense oligonucleotide designed to prevent the expression of MDM2. The compound, called GEM 240, is still in preclinical development.
