The protein KRAS has for decades been considered a holy grail of cancer drug discovery. For most of that time, it has also been considered undruggable. Since 2018, five compounds have entered the clinic targeting a single mutant form of KRAS, G12C. Here, we review each of these compounds along with additional approaches to targeting this and other mutants. Remaining challenges include expanding the identification of inhibitors to a broader range of known mutants and to conformations of the protein more likely to avoid development of resistance.

中文翻译：

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靶向突变 KRAS。

几十年来，KRAS 蛋白一直被认为是癌症药物发现的圣杯。在那段时间的大部分时间里，它也被认为是不可成药的。自 2018 年以来，针对 KRAS 的单一突变形式 G12C 的五种化合物已进入临床。在这里，我们回顾了这些化合物中的每一种，以及针对该突变体和其他突变体的其他方法。剩下的挑战包括将抑制剂的鉴定范围扩大到更广泛的已知突变体和更可能避免产生抗性的蛋白质构象。