Researchers from the Wellcome Trust Sanger Institute have launched COSMIC-3D, a tool that allows scientists to explore how cancer mutations affect the structure and function of more than 8,000 human proteins. They hope COSMIC-3D, which is freely available on the web, will facilitate the design of new cancer drugs.

Many cancer researchers depend on the Catalogue of Somatic Mutations in Cancer (COSMIC) to quickly identify what is known about a mutation, from its prevalence in different tumor types to the biological pathways it affects (cancer.sanger.ac.uk/cosmic). Now, they can use COSMIC-3D to explore how the mutations in the COSMIC database affect the structure and function of more than 8,000 human proteins (cancer.sanger.ac.uk/cosmic3d).

“With the vast majority of disease-causing mutations identified in coding sequences, we wanted to create a system where these mutations could be easily explored in their structural environment,” says Simon Forbes, PhD, head of COSMIC at the Wellcome Trust Sanger Institute in the UK. Having spent years developing the COSMIC database, his group now seeks to “highlight an enormous range of known and novel targets, to explore novel precision drug design.”

To ensure that the tool would be useful to researchers working on drug design, Forbes and Harry Jubb, PhD, at Sanger partnered with Astex Pharmaceuticals (Cambridge, UK), which specializes in structure-based drug discovery.

“For small-molecule therapies, a prerequisite for drug binding is to have a concave binding pocket on a protein target, into which a small molecule can be designed to modify the protein's function,” Forbes explains. To visualize the molecule's predicted drug binding sites and pockets, where known cancer mutations occur in relation to those areas, and how the mutations are likely to alter these parts of the protein, COSMIC-3D users simply need to enter the protein of interest.

Cancer researchers are beginning to explore the catalogue, which was launched in May. “I think it's great that COSMIC is expanding to think about 3-D protein structure and what this can contribute to the analysis of genetic mutations in cancer,” says Rachel Karchin, PhD, a computational biologist at Johns Hopkins University in Baltimore, MD. “You can learn so much about protein function from looking at protein structure. Often, we try to interpret the functional importance of somatic mutations by their proximity to things like binding sites. What you miss when you don't look at 3-D protein structure is that things that appear to be far apart in the sequence may be very close together when the protein is folded.”

Karchin notes that COSMIC-3D joins several other tools for exploring cancer mutations in 3-D, including 3D Hotspots (3dhotspots.org), Cancer3D (www.cancer3d.org), and MuPIT Interactive (mupit.icm.jhu.edu/MuPIT_Interactive), which was created by her lab. However, she says that it has been challenging to get scientists who are not structural biology experts interested in this area. For this reason, she suggests that developers who want to appeal to the broader research community ask, “Could somebody who does not know structural biology benefit from this tool?”

Forbes hopes that for COSMIC-3D, the answer is yes. “We would like to encourage cancer researchers and clinicians to explore the millions of mutations in the COSMIC database from our new perspective.” –Kristin Harper

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.