New molecule could offer targeted therapies against tumour growth

Scientists have discovered a new drug with great promise for the fight against cancer. Called SSR128129E, or SSR for short, it binds to receptors on the surfaces of cancer cells and stops the growth of blood vessels within tumours. It offers a targeted therapy that starves tumours of blood without the side-effects common with many cancer therapies.

If it successfully passes human tests, the drug, developed by a team led by pharmaceutical company Sanofi and including Francesco Gervasio (UCL Chemistry and Institute of Structural and Molecular Biology), could be on the market within a decade, and could help target a range of cancers including bladder cancer.

Cancer therapies come in different forms, but many are marred by lack of targeting. Drugs which are toxic to cancer cells are, more often than not, also toxic to a patient's healthy cells. One of the main objectives for drug designers is to come up with treatments which target unique properties of cancerous cells without hurting healthy tissue, and therefore reducing the harmful side-effects common in many cancer treatments.

The compact extracellular immunoglobulin-like domain D3 has to undergo a surprising conformational change to be able to bind to SSR. This state was invisible to X-ray crystallography and nuclear magnetic resonance. Thus, it was only with complex computer simulations that it was possible to understand its details. The structural details of the new cavity were subsequently used to design more potent (and/or selective) derivatives of SSR. Image credit: F. Gervasio (UCL Chemistry)

"A promising area in cancer research in recent years has been the search for drugs that target the growth of blood vessels within tumours," says Francesco Gervasio (UCL Chemistry), co-author of two new papers in the journal Cancer Cell which outline this research. "Cancerous tumours have a huge appetite for blood, and their continued growth depends on blood vessels. But success at targeting these has been mixed because cancer cells mutate fast, giving them a mechanism to escape the drugs targeted at them."

One way of halting the growth of blood vessels in tumours is by binding with, and physically blocking the intracellular active site of receptors on the surfaces of cells, which stops their catalytic activity, which would trigger the creation of new blood vessels. However, doing this in practice has proven to have serious pitfalls because the receptors on the tumour cells mutate quickly: they are a moving target, and a drug which can bind with them now may not do in future.

The new drug bypasses the pitfalls by targeting cancer cells in a new way. Instead of targeting the main ('orthosteric') receptors in the cells, they target a slower-mutating site on the surface of the cell ('allosteric'). SSR does not physically block the active site, but it inhibits the dimerization of the receptor, selectively blocking the pathway through which new blood vessel growth is triggered. Allosteric drugs have significant therapeutic advantages over traditional 'orthosteric' drugs, including greater safety and less toxicity. SSR, as the first example of a small molecule inhibiting an important class of pharmaceutical targets (receptor tyrosine kinases), could open the avenue to a new generation of smart anti-cancer drugs.

Key to this research was simulating the property of the drug in one of the largest supercomputers available, work carried out by Gervasio. "Without modelling the drug in a supercomputer, it would have been impossible to know how it worked," Gervasio explains. "It was a very complex process which represents four years of work, but it shows a very promising avenue that is open for similar research in future."

The drug has been tested in mice so far. As with all novel drugs, it will have to undergo comprehensive tests in humans to determine its safety and effectiveness before it is introduced.

Notes

The research appears in two papers in the April 15 issue of the journal Cancer Cell:

Inhibition of Tumor Angiogenesis and Growth by a Small-Molecule Multi-FGF Receptor Blocker with Allosteric Properties
Molecular Mechanism of SSR128129E, an Extracellularly Acting, Small-Molecule Allosteric Inhibitor of FGF Reception Signalling

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Researcher profile

Francesco L. Gervasio

Science contact

Francesco Luigi Gervasio
UCL Department of Chemistry
020 7679 3215
f.l.gervasio@ucl.ac.uk

Media contact

Oli Usher
UCL Faculty of Mathematical and Physical Sciences
020 7679 7964
o.usher@ucl.ac.uk

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