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KRAS inhibitors, approved

机译：喀斯特抑制剂,批准

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摘要

The rapid progression of KRAS(G12C) inhibitors from preclinical characterization to the clinic has radically changed the perception of the KRAS oncogene as an undruggable target. Here we discuss ongoing and future possibilities for developing therapies using these inhibitors in clinical settings. KRAS guanosine triphosphate hydrolase (GTPase) regulates downstream signaling through the engagement of effectors with high affinity toward its active, GTP-bound conformation. GTP hydrolysis is catalyzed by three key domains within the KRAS protein: the p-loop (residues 10-17), switch I (residues 30-38) and switch II (residues 60-76). KRAS activation is tightly regulated by the guanine nucleotide exchange factor SOS1, which promotes the exchange of GDP for GTP to activate the inactive GDP-bound KRAS. Downstream effectors, including RAF kinases, PI3K, RALA and RALB among others, contain KRAS-binding domains. Single amino acid substitutions in the KRAS GTPase p-loop domain, such as those involving the G12 (D/C/V/R/A/S) or G13 (D/C/V) residues, result in the constitutive activation of the KRAS oncoprotein by hindering its capacity to hydrolyze GTP.
机译：的快速发展喀斯特(G12C)抑制剂从临床表征到诊所从根本上改变了人们对喀斯特吗无药可治癌基因作为目标。讨论正在进行的和未来的可能性发展中使用这些抑制剂治疗临床设置。水解酶(GTPase)调节下游信号通过效应器与高的参与亲和力对其活跃,GTP-bound构象。三个关键领域内喀斯特蛋白质:p-loop(残留- 17),换我(残留物此前)和第二开关(残留60 - 76)。激活是由鸟嘌呤严格监管的SOS1核苷酸交换因素,促进三磷酸鸟苷的交易所占GDP的激活蛋白喀斯特。包括英国皇家空军激酶、PI3K RALA和RALB其他人,包含KRAS-binding域。在喀斯特GTPase氨基酸替换p-loop域,如涉及(D / C / V / R / A / S)或G13 (D / C / V)残留,导致喀斯特的本构激活肿瘤蛋白通过阻碍其能力水解三磷酸鸟苷。

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