Scientists Develop Monobody That Inhibits Activity of Two RAS Proteins

Researchers at the University of Illinois at Chicago (UIC), together with collaborators, have identified a new way to block the action of genetic mutations found in nearly 30 percent of all cancers. Mutations in genes for the RAS family of proteins are present in nearly 90 percent of pancreatic cancers and are also highly prevalent in colon cancer, lung cancer, and melanoma, the most dangerous kind of skin cancer. The group of RAS proteins includes three members, K-RAS, H-RAS, and N-RAS. The prevalence of RAS mutations in human cancers and the dependence of tumors on RAS for survival has made RAS a prime target for cancer research and drug discovery. Scientists and drug developers have long studied RAS oncogenes hoping to find a new treatment for cancer, but they have not yet been able to identify drugs that safely inhibit the oncogene’s activity. John O'Bryan (photo), Ph.D., Associate Professor of Pharmacology in the UIC College of Medicine, led a team of researchers that took a different approach to studying RAS, and discovered that a synthetic binding protein they call "NS1 monobody," which they created in the lab, can block the activity of the RAS proteins. "We did not look for a drug or specifically for an inhibitor," said Dr. O'Bryan, who is also a member of the University of Illinois Cancer Center and holds an appointment at the Jesse Brown VA Medical Center in Chicago. "We used monobody technology, a type of protein-engineering technology, to identify regions of RAS that are critical for its function." Unlike conventional antibodies, monobodies are not dependent on their environment and can be readily used as genetically encoded inhibitors, Dr. O'Bryan said. "The beauty of the technology is that when a monobody binds a protein, it usually works as an inhibitor of that protein," he said.
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