Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, United States; Ralph H. Johnson VA Medical Center, Charleston, SC, 29401, United States.
Pharmacol Res. 2019 Jan;139:503-511. doi: 10.1016/j.phrs.2018.10.021. Epub 2018 Oct 23.
RAS has long been viewed as undruggable due to its lack of deep pockets for binding of small molecule inhibitors. However, recent successes in the development of direct RAS inhibitors suggest that the goal of pharmacological inhibition of RAS in patients may soon be realized. This review will discuss the role of RAS in cancer, the approaches used to develop direct RAS inhibitors, and highlight recent successes in the development of novel RAS inhibitory compounds that target different aspects of RAS biochemistry. In particular, this review will discuss the different properties of RAS that have been targeted by various inhibitors including membrane localization, the different activation states of RAS, effector binding, and nucleotide exchange. In addition, this review will highlight the recent success with mutation-specific inhibitors that exploit the unique biochemistry of the RAS(G12C) mutant. Although this mutation in KRAS accounts for 11% of all KRAS mutations in cancer, it is the most prominent KRAS mutant in lung cancer suggesting that G12C-specific inhibitors may provide a new approach for treating the subset of lung cancer patients harboring this mutant allele. Finally, this review will discuss the involvement of dimerization in RAS function and highlight new approaches to inhibit RAS by specifically interfering with RAS:RAS interaction.
RAS 长期以来一直被认为是不可成药的，因为它缺乏与小分子抑制剂结合的深口袋。然而，最近在直接 RAS 抑制剂开发方面的成功表明，在患者中实现 RAS 药理学抑制的目标可能很快就会实现。这篇综述将讨论 RAS 在癌症中的作用，开发直接 RAS 抑制剂所采用的方法，并强调最近在开发靶向 RAS 生化不同方面的新型 RAS 抑制化合物方面的成功。特别是，这篇综述将讨论不同的 RAS 特性，包括膜定位、RAS 的不同激活状态、效应物结合和核苷酸交换，这些特性已被各种抑制剂靶向。此外，这篇综述将突出最近具有突变特异性抑制剂的成功，这些抑制剂利用 RAS(G12C)突变的独特生物化学特性。尽管 KRAS 中的这种突变占癌症中所有 KRAS 突变的 11%，但它是肺癌中最突出的 KRAS 突变，这表明 G12C 特异性抑制剂可能为携带这种突变等位基因的肺癌患者亚群提供一种新的治疗方法。最后，这篇综述将讨论二聚化在 RAS 功能中的作用，并强调通过特异性干扰 RAS:RAS 相互作用来抑制 RAS 的新方法。
