title: K-Ras protein as a drug target.
abstract: K-Ras proteins are major drivers of human cancers, playing a direct causal role in about one million cancer cases/year. In cancers driven by mutant K-Ras, the protein is locked in the active, GTP-bound state constitutively, through a defect in the off-switch mechanism. As such, the mutant protein resembles the normal K-Ras protein from a structural perspective, making therapeutic attack extremely challenging. K-Ras is a member of a large family of related proteins, which share very similar GDP/GTP-binding domains, making specific therapies more difficult. Furthermore, Ras proteins lack pockets to which small molecules can bind with high affinity, with a few interesting exceptions. However, new insights into the structure and function of K-Ras proteins reveal opportunities for intervention that were not appreciated many years ago, when efforts were launched to develop K-Ras therapies. Furthermore, K-Ras undergoes post-translational modification and interactions with cellular signaling proteins that present additional therapeutic opportunities, such as specific binding to calmodulin and regulation of non-canonical Wnt signaling.
authors.affiliation: UCSF Helen Diller Family Comprehensive Cancer Center, 1450 3rd Street, San Francisco, CA, 94158-9001, USA. mccormick@cc.ucsf.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: McCormick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D060066:Protein Interaction Maps / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D018631:ras Proteins
keywords: Cancer; K-Ras proteins; K-Ras therapies