K-Ras protein as a drug target

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.