1] Max Planck Institute of Molecular Physiology, Dortmund, Germany. [2] Department of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany.
1] Department of Chemistry and Chemical Biology, Technical University Dortmund, Dortmund, Germany. [2] Chemical Genomics Centre of the Max Planck Society, Dortmund, Germany.
Nat Chem Biol. 2014 Aug;10(8):613-22. doi: 10.1038/nchembio.1560. Epub 2014 Jun 15.
Despite intense efforts in pharmaceutical industry and academia, a therapeutic grip on oncogenic Ras proteins has remained elusive. Mutated Ras is associated with ~20-30% of all human cancers often not responsive to established therapies. In particular, K-Ras, the most frequently mutated Ras isoform, is considered one of the most important but 'undruggable' targets in cancer research. Recently, new cavities on Ras for small-molecule ligands were identified, and selective direct targeting of mutated K-Ras(G12C) has become possible for what is to our knowledge the first time. In addition, impairment of Ras spatial organization, in particular via targeting the prenyl-binding Ras chaperone PDEδ, has opened a fresh perspective in anticancer research. These recent advances fuel hopes for the development of new drugs targeting Ras.
尽管制药业和学术界做出了巨大努力，但对于致癌 Ras 蛋白的治疗方法仍然难以捉摸。突变型 Ras 与约 20-30%的所有人类癌症相关，通常对现有疗法没有反应。特别是，K-Ras 是最常突变的 Ras 同工型之一，被认为是癌症研究中最重要但“不可成药”的靶点之一。最近，在 Ras 上发现了小分子配体的新结合腔，并且首次有可能对突变的 K-Ras(G12C)进行选择性直接靶向。此外，通过靶向 prenyl-binding Ras chaperone PDEδ 来破坏 Ras 的空间组织，为癌症研究开辟了新的视角。这些最新进展为开发针对 Ras 的新药带来了希望。
