|Breaking a Pocket of Resistance in the Fight Against Cancer|
|Thursday, 12 December 2013 11:55|
Mutations in the protein K-RAS are a very common cause for certain types of human cancers and are generally associated with a poor response to standard therapies. RAS, an abbreviation of Rat Sarcoma, is a nucleotide binding protein that responds to chemical signals (nucleotides). When in the "on" state, RAS activates other proteins, resulting in a cascade of biochemical processes; in the "off" state, RAS remains inactive. Mutations in the RAS gene can create an imbalance between the activation and deactivation of the RAS protein, a causal factor in approximately 30% of all cancers. In some cases it is even higher, as in pancreatic cancer where mutations in RAS cause 90% of all cancers. This makes RAS a prime target for drug discovery, but it has resisted approaches until now, even to the point of being considered "undruggable" by many pharmaceutical companies. Researchers from University of California, San Francisco have now made an important first step by the discovery and design of inhibitors that specifically bind to a RAS mutant associated with lung cancer. Initial lead candidates were explored and optimized via x-ray crystallographic methods utilizing the HHMI-funded Beamline 8.2.1 at the Advanced Light Source. Structural analyses have revealed that this new class of inhibitors binds to a previously unknown allosteric pocket, resulting in a change in nucleotide binding specificity of RAS as well as disrupting known protein-protein interactions associated with downstream, cancer-related biochemical processes. Although the newly discovered inhibitors are still far away from novel therapeutics, the opportunities created by this research will ultimately aid in the taming of RAS.
Work performed on ALS Beamline 8.2.1
Citation: J. Ostrem, U. Peters, M. Sos, J. Wells, and K. Shokat, "K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions," Nature (2013), DOI: 10.1038/nature12796
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