K-Ras protein as a drug target

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• 作者：Frank McCormick
• 关键词：K ; Ras proteins ; Cancer ; K ; Ras therapies
• 刊名：Journal of Molecular Medicine
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：94
• 期：3
• 页码：253-258
• 全文大小：863 KB
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Molecular Medicine
  Internal Medicine
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-1440

文摘

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.