Design, synthesis, and evaluation of 4(1H)-quinolinone and urea derivatives as KRASG12C inhibitors with potent antitumor activity against KRAS-mutant non-small cell lung cancer
Design, synthesis, and evaluation of 4(1H)-quinolinone and urea derivatives as KRASG12C inhibitors with potent antitumor activity against KRAS-mutant non-small cell lung cancer
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4(1H)-喹啉酮和尿素衍生物的设计、合成和评估作为 KRASG12C 抑制剂，对 KRAS 突变非小细胞肺癌具有有效的抗肿瘤活性
DOI：
10.1016/j.ejmech.2022.114808
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发表时间：
2022
影响因子：
6.7
通讯作者：
Yisheng Lai
中科院分区：
文献类型：
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作者：
Rongjie Cheng;Xiashi Lv;Huagang Bu;Qiaoliang Xu;Jianzhuang Wu;Kexin Xie;Jiaqi Tang;Lei Wang;Jian Zhuang;Yihua Zhang;Yaliang Zhang;Chao Yan;Yisheng Lai
KRASG 12 C是非小细胞肺癌（NSCLC）中最常见的KRAS突变，并已成为一个有前途的治疗靶点。本文以已报道的KRASG 12 C抑制剂SH-9为基础，设计了两个系列的4（1H）-喹啉酮和脲类化合物。在细胞活力测定中，许多化合物对具有KRASG 12 C突变的人NSCLC细胞显示出显著的生长抑制活性。化合物20 a在KRASG 12 C突变型NCI-H358细胞中表现出0.5 μM的IC 50值，选择性是KRASWTNCI-H2228细胞的21倍。LC-MS分析表明，化合物14 c、14和20 acotoxin与KRASG 12 C结合，而不是与KRASWT结合。此外，这些化合物可以通过阻断SOS 1介导的GDP/GTP交换，显着将KRASG 12 C捕获在非活性状态。此外，用20剂量依赖性地处理NCI-H358而不是NCI-H2228细胞减少了KRAS下游效应物ERK和AKT的磷酸化。重要的是，20 a通过抑制KRASG 12 C信号传导显著抑制NCI-H358异种移植模型中的肿瘤生长。这些结果表明，20是一个有前途的候选人值得进一步研究。
KRASG12Cis the most prevalent KRAS mutation in non-small cell lung cancer (NSCLC) and has emerged as a promising therapeutic target. Herein, two series of novel 4(1H)-quinolinone and urea compounds were designed based on the reported KRASG12Cinhibitor SH-9. Many compounds showed significantly growth inhibitory activity against human NSCLC cells with KRASG12Cmutation in cell viability assays. Compound20aexhibited an IC50value of 0.5 μM in KRASG12C-mutant NCI–H358 cells with 21-fold selectivity over KRASWTNCI–H2228 cells. LC-MS analysis indicated that compounds14c,14hand20acovalently bound to KRASG12Crather than KRASWT. Moreover, these compounds could remarkably trap KRASG12Cin its inactive state by blocking SOS1-mediated GDP/GTP exchange. Furthermore, treatment of NCI–H358 but not NCI–H2228 cells with20adose-dependently reduced the phosphorylation of KRAS downstream effectors ERK and AKT. Importantly,20asignificantly inhibited tumor growth in NCI–H358 xenograft models by suppressing KRASG12Csignalling. These results indicate that20ais a promising candidate worthy of further investigation.