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Therapeutic targeting of RAS: New hope for drugging the "undruggable".
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research ( IF 5.1 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.bbamcr.2019.118570
Imran Khan 1 , J Matthew Rhett 1 , John P O'Bryan 1
Affiliation  

RAS is the most frequently mutated oncogene in cancer and a critical driver of oncogenesis. Therapeutic targeting of RAS has been a goal of cancer research for more than 30 years due to its essential role in tumor formation and maintenance. Yet the quest to inhibit this challenging foe has been elusive. Although once considered "undruggable", the struggle to directly inhibit RAS has seen recent success with the development of pharmacological agents that specifically target the KRAS(G12C) mutant protein, which include the first direct RAS inhibitor to gain entry to clinical trials. However, the limited applicability of these inhibitors to G12C-mutant tumors demands further efforts to identify more broadly efficacious RAS inhibitors. Understanding allosteric influences on RAS may open new avenues to inhibit RAS. Here, we provide a brief overview of RAS biology and biochemistry, discuss the allosteric regulation of RAS, and summarize the various approaches to develop RAS inhibitors.

中文翻译:

RAS 治疗靶向:给“不可成药”药物治疗的新希望。

RAS 是癌症中最常突变的癌基因,也是肿瘤发生的关键驱动因素。由于 RAS 在肿瘤形成和维持中的重要作用,30 多年来,RAS 的治疗靶向一直是癌症研究的目标。然而,抑制这个具有挑战性的敌人的努力一直难以实现。尽管一度被认为是“不可成药”的,但直接抑制 RAS 的斗争最近随着专门针对 KRAS(G12C) 突变蛋白的药物的开发取得了成功,其中包括第一个进入临床试验的直接 RAS 抑制剂。然而,这些抑制剂对 G12C 突变肿瘤的适用性有限,需要进一步努力以确定更广泛有效的 RAS 抑制剂。了解变构对 RAS 的影响可能会开辟抑制 RAS 的新途径。在这里,我们简要概述了 RAS 生物学和生物化学,讨论了 RAS 的变构调节,并总结了开发 RAS 抑制剂的各种方法。
更新日期:2019-11-01
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