Heidi Ledford in Nature:
When Stephen Fesik left the pharmaceutical industry to launch an academic drug-discovery laboratory, he drew up a wanted list of five of the most important cancer-causing proteins known to science. These proteins drive tumour growth but have proved to be a nightmare for drug developers: they are too smooth, too floppy or otherwise too finicky for drugs to bind to and block. In the parlance of the field, they are 'undruggable'.
One of the first culprits that Fesik added to his list was a protein family called Ras. For more than 30 years, it has been known that mutations in the genes that encode Ras proteins are among the most powerful cancer drivers. Ras mutations are found in some of the most aggressive and deadly cancers, including up to 25% of lung tumours and about 90% of pancreatic tumours. And for some advanced cancers, tumours with Ras mutations are associated with earlier deaths than tumours without them.Decades of research have yet to yield a drug that can safely curb Ras activity. Past failures have driven researchers from the field and forced pharmaceutical companies to abandon advanced projects. But Fesik's laboratory at Vanderbilt University in Nashville, Tennessee, and a handful of other teams have set their sights anew on the proteins. They are armed with improved technology and a better understanding of how Ras proteins work. Last year, the US National Cancer Institute launched the Ras Initiative, a US$10-million-a-year effort to find new ways to tackle Ras-driven cancers. And researchers are already uncovering compounds that, with tweaking, could eventually yield the first drugs to target Ras proteins.