Blocking BRAF: developing enzyme inhibitors as cancer drugs

How Wellcome Trust-supported work at the Institute for Cancer Research, London could lead to a new drug to fight melanoma and other cancers.

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Running time: 4 min 13 s.
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In June 2002, a team from the Wellcome Trust Sanger Institute published a paper in the journal 'Nature' that showed that a particular genetic mutation occurs in 66 per cent of malignant melanomas. The gene, BRAF, is mutated in around 7 per cent of human cancers, including some colorectal, ovarian and thyroid cancers.

The presence of mutated BRAF in such a high proportion of melanoma cases, and in such a wide range of human cancers, led researchers to examine the protein as a target for anticancer therapy.

These researchers include Richard Marais, one of the authors of the landmark 2002 paper and now Professor of Molecular Oncology at the Institute of Cancer Research in London. He and Caroline Springer, Professor of Biological Chemistry at the Institute, have received Technology Transfer funding to develop drug-like inhibitors of BRAF, including a Strategic Translation Award made in 2005/06.

BRAF is a protein kinase, an enzyme that alters the effects of other proteins by adding a chemical group (a phosphate) to them. As it is a key part of a signalling pathway in the cell that leads to cell proliferation, if it is made continuously active (by a mutation, for example), then cells can multiply without limit, which can lead to cancer.

BRAF's cancer-causing mutations occur in its kinase domain, the region that modifies other proteins. Of the 40 different BRAF mutations implicated in human cancers, over 90 per cent comprise a change at a single base in the DNA sequence, which causes the 600th amino acid in the protein to change to another.

"We know the exact order of amino acids in the protein and, thanks to the work of Richard Marais, Professor David Barford and their colleagues, we have the structure of BRAF as well as its shape," says Professor Springer. "We can use this information to try to make compounds that interact with the kinase domain and block it."

The production of therapeutics that are targeted to specific mutated proteins will ultimately mean that doctors are better placed to tailor treatment to the individual patient. If a BRAF mutation is found in a patient, then a BRAF inhibitor could be employed. If, on the other hand, no BRAF mutation is detected, the patient could be spared drugs that likely would not help them.

The drug discovery approach Professors Springer and Marais are taking is based on high-throughput screens: large-scale, automated sets of experiments that test series of compounds at a time for each compound's ability to block the activity of BRAF.

Although the methods used at the Institute of Cancer Research are similar to those used in drug discovery programmes elsewhere in academia and industry, Professor Marais thinks there's something unique about the Institute that makes a vital difference to the efficiency and effectiveness of the process.

"To me, academia offers a unique opportunity to get chemists, pharmacologists and biologists working closely together within a single research environment" he says. "What's particularly unusual here at the Institute is that the discovery was made by people that work here. It is rare to be in a situation where you discover a drug target and then have the capability to develop a drug using that information."

This proximity between the biologists and chemists can also help speed up the drug discovery process. As Professor Marais's team makes new discoveries, it can introduce them to the drug discovery programme straight away. Further along the discovery process, the team remains ready to help provide a biological context for the drugs made.

"It's really about enriching the biology that's already known," says Professor Marais. "For example, any new discoveries that might make you worried about your own compound can be tested very quickly. We can support what's going on in terms of the chemistry - it’' an iterative process."

"In terms of the kinase inhibitors, we're nearing the end-stage," says Professor Springer. Both teams have been working together to develop new assays to test how selective the BRAF inhibitors are compared to drugs that target other kinases. This is important as kinases control a number of vital processes in the body, so researchers must be sure what a particular drug is doing throughout the whole system. The researchers will select a pre-clinical candidate in early 2009.

References

Davies H et al. Mutations of the BRAF gene in human cancer. Nature 2002;417(6892):949-54.

Wan PTC et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004;116(6):855-867.

Newbatt Y et al. Identification of inhibitors of the kinase activity of oncogenic V600E BRAF in an enzyme cascade high-throughput screen. J Biomol Screen 2006;11(2):145-154.

Niculescu-Duvaz I et al. Novel inhibitors of the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) based on a 2,6-disubstituted pyrazine scaffold. J Med Chem 2008;51(11):3261-3274.

Gray-Schopfer V et al. Melanoma biology and new targeted therapy. Nature 2007;445(7130):851-857.