Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor
Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor
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DOI：
10.1016/j.cell.2018.01.006
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发表时间：
2018-01-25
期刊：
影响因子：
64.5
通讯作者：
Liu, Yi
中科院分区：
文献类型：
--
作者：
Janes, Matthew R.;Zhang, Jingchuan;Liu, Yi
KRAS（G12 C）最近被鉴定为通过等位基因特异性共价靶向Cys-12附近的诱导型变构开关II口袋（S-IIP）而具有潜在的可药用性。这种方法的成功需要KRAS（G12 C）在其活性GTP和非活性GDP构象之间的活性循环，因为S-IIP的可接近性仅限于GDP结合状态。这种策略被证明在体外抑制突变型KRAS是可行的;然而，不确定这种方法是否会转化为体内。在这里，我们描述了ARS-1620的基于结构的设计和鉴定，ARS-1620是一种对KRAS（G12 C）具有高效力和选择性的共价化合物。ARS-1620实现了快速和持续的体内靶标占据，以诱导肿瘤消退。我们使用ARS-1620来剖析致癌KRAS依赖性，并证明单层培养形式显著低估了体内KRAS依赖性。这项研究提供了体内证据，表明突变型KRAS可以被选择性靶向，并揭示ARS-1620代表了新一代KRAS（G12 C）特异性抑制剂，具有很好的治疗潜力。
KRAS(G12C) was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRAS(G12C) between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRAS(G12C). ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRAS(G12C)-specific inhibitors with promising therapeutic potential.