Pharmacological targeting of RAS: Recent success with direct inhibitors.
Pharmacological targeting of RAS: Recent success with direct inhibitors.
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DOI：
10.1016/j.phrs.2018.10.021
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发表时间：
2019-01
影响因子：
9.3
通讯作者：
O'Bryan JP
中科院分区：
文献类型：
--
作者：
O'Bryan JP
RAS长期以来被认为是不可药物的，因为它缺乏与小分子抑制剂结合的深度口袋。然而，最近在直接RAS抑制剂开发方面的成功表明，药物抑制患者RAS的目标可能很快就会实现。本文将讨论RAS在癌症中的作用，用于开发直接RAS抑制剂的方法，并重点介绍最近在开发针对RAS生物化学不同方面的新型RAS抑制化合物方面取得的成功。特别是，本文将讨论各种抑制剂所靶向的RAS的不同特性，包括膜定位、RAS的不同激活状态、效应物结合和核苷酸交换。此外，本综述将重点介绍利用RAS（G12C）突变体独特的生物化学特性的突变特异性抑制剂的最新成功。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治疗含有这种突变等位基因的肺癌患者亚群提供了一种新的方法。最后，本文将讨论二聚化在RAS功能中的作用，并重点介绍通过特异性干扰RAS:RAS相互作用来抑制RAS的新方法。
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.
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影响因子：
3.7
作者：
Grant, Barry J.;Lukman, Suryani;Gorfe, Alemayehu A.
通讯作者：
Gorfe, Alemayehu A.
影响因子：
4.3
作者：
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通讯作者：
BARRITT, GJ
DOI：
10.1073/pnas.0903907107
发表时间：
2010-01-19
影响因子：
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作者：
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通讯作者：
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作者：
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作者：
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通讯作者：
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