| 毛梅#,和琦,陈璇,等.大鼠肉瘤病毒癌基因同源物抑制剂的设计、合成及活性评价[J].中国海洋药物,2026,(3):-. |
| 大鼠肉瘤病毒癌基因同源物抑制剂的设计、合成及活性评价 |
| Design, synthesis and evaluation of the activity of KRAS inhibitors |
| 投稿时间：2025-03-12 修订日期：2025-04-14 |
| DOI： |
| 中文关键词: 大鼠肉瘤病毒癌基因同源物 大鼠肉瘤病毒癌基因同源物G12D 大鼠肉瘤病毒癌基因同源物抑制剂 抗肿瘤细胞增殖活性 |
| English Keywords:KRAS KRAS G12D KRAS inhibitor antitumor cell proliferation activity |
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| 中文摘要: |
| 目的 以化合物243为先导化合物,围绕吡啶并嘧啶环核心骨架构建一系列新型KRAS抑制剂并进行活性评价。方法 以2-氯-3-氟异烟酸为起始原料,通过重排反应、脱保护、取代等反应合成KRAS抑制剂12a~12f,并测定其在KRAS G12D突变的人胰腺癌细胞AsPC-1、胃腺癌细胞AGS中的增殖抑制活性以及ERK1/2磷酸化抑制活性。结果 合成共计6个KRAS G12D抑制剂12a~12f，相比于阳性化合物243，所合成化合物对AsPC-1细胞和AGS细胞的增殖抑制活性较弱，但免疫印迹实验结果显示化合物12b有效抑制了KRAS下游蛋白p-ERK1/2的水平，具有抑制KRAS信号通路激活从而抑制肿瘤恶性进展的潜力。结论 本研究通过陆源小分子与海洋药物片段的创新融合，不仅拓展了KRAS抑制剂的构效关系，还为KRAS靶向药物研发提供了新结构模板。化合物12b展现出良好的抗肿瘤潜力，后续将通过结构优化进一步提升其活性与成药性，为KRAS突变肿瘤的临床治疗提供新策略。 |
| English Summary: |
| Objective Using compound 243 as the lead compound, a series of novel KRAS inhibitors were constructed around the core skeleton of pyridopyrimidine ring and evaluated for activity. Methods KRAS inhibitors 12a-12f were synthesized by rearrangement reaction, deprotection and substitution reaction using 2-chloro-3-fluoroisonicotinic acid as the starting material. The proliferation inhibitory activity and ERK1/2 phosphorylation inhibitory activity of KRAS inhibitors 12a-12f in KRAS G12D mutant human pancreatic cancer cell AsPC-1 and gastric adenocarcinoma cell AGS were determined. Results A total of 6 KRAS G12D inhibitors 12a-12f were synthesized. Compared with the positive compound 243, the synthesized compounds had weaker inhibitory activity on the proliferation of AsPC-1 cells and AGS cells. However, the results of Western blotting showed that compound 12b effectively inhibited the level of KRAS downstream protein p-ERK1/2, and had the potential to inhibit the activation of KRAS signaling pathway and thus inhibit the malignant progression of tumors.Conclusion In this study, the innovative fusion of terrestrial small molecules and marine drug fragments not only expands the structure-activity relationship of KRAS inhibitors, but also provides a new structural template for the development of KRAS targeted drugs. Compound 12b shows good anti-tumor potential, and its activity and druggability will be further improved through structural optimization, which will provide a new strategy for the clinical treatment of KRAS mutant tumors. |
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