Frontier Medicines Corporation, 151 Oyster Point Blvd., 2nd Floor, South San Francisco, CA, 94080, USA.
Frontier Medicines Corporation, 151 Oyster Point Blvd., 2nd Floor, South San Francisco, CA, 94080, USA.
Curr Opin Chem Biol. 2021 Jun;62:101-108. doi: 10.1016/j.cbpa.2021.02.010. Epub 2021 Apr 7.
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.
几十年来，蛋白 KRAS 一直被认为是癌症药物发现的圣杯。在这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，已有五种化合物针对 KRAS 的单一突变形式 G12C 进入临床。在这里，我们回顾了这些化合物中的每一种，以及针对这种和其他突变体的其他方法。仍然存在的挑战包括将抑制剂的鉴定扩展到更广泛的已知突变体，并针对更有可能避免产生耐药性的蛋白质构象。
