雜志名稱：Bioorganic Chemistry
影響因子：5.1
文章題目：Discovery, optimization and biological activity evaluation of genipin derivatives as potential KRAS G12D inhibitors
DOI: 10.1016/j.bioorg.2024.107460
第一作者：Ran Sun , Yangfan Hu , Xiangwen Liu , Yingjun Lin , Dan Lv , Wei Li , Lei Fu , Faqin Jiang
作者單位：
上海交通大學(xué)藥學(xué)院
西安交通利物浦大學(xué)藥學(xué)院
引用YOBIBIO產(chǎn)品：
U11-020A 優(yōu)級胎牛血清 Superior FBS
文章摘要：
A series of genipin derivatives were designed and synthesized as potential inhibitors targeted KRAS G12D mutation. The majority of these compounds demonstrated potential antiproliferative effects against KRAS G12D mutant tumor cells (CT26 and A427). Notably, seven compounds exhibited the anticancer effects with IC values ranging from 7.06 to 9.21 μM in CT26 (KRAS) and A427 (KRAS) cells and effectively suppressed the colony formation of CT26 cells. One representative compound was selected for further investigation into biological activity and action mechanisms. markedly induced apoptosis in CT26 cells in a concentration-dependent manner. Moreover, elevated the levels of reactive oxygen species (ROS) in tumor cells and exhibited a modulatory effect on the KRAS signaling pathway, thereby inhibiting the activation of downstream phosphorylated proteins. The binding affinity of to KRAS G12D protein was further confirmed by the surface plasmon resonance (SPR) assay with a binding K of 157 μM. also exhibited notable anticancer efficacy in a nude mice tumor model. The relative tumor proliferation rate (T/C) of the experimental group (50 mg/kg) was 31.04 % (P < 0.05), while maintaining a commendable safety profile.
設(shè)計并合成了一系列吉尼平衍生物，作為KRAS G12D突變的潛在抑制劑。這些化合物中的大多數(shù)對KRAS G12D突變腫瘤細胞(CT26和A427)具有潛在的抗增殖作用。值得注意的是，7種化合物在CT26 (KRAS)和A427 (KRAS)細胞中表現(xiàn)出抗癌作用，IC值在7.06 ~ 9.21μM之間，并有效抑制CT26細胞的集落形成。選擇了一種具有代表性的化合物進行生物活性和作用機制的進一步研究。以濃度依賴性方式顯著誘導(dǎo)CT26細胞凋亡。此外，提高腫瘤細胞中的活性氧(ROS)水平，并對KRAS信號通路表現(xiàn)出調(diào)節(jié)作用，從而抑制下游磷酸化蛋白的激活。表面等離子體共振(SPR)實驗進一步證實了與KRAS G12D蛋白的結(jié)合親和力，結(jié)合K為157μM。在裸鼠腫瘤模型中也有明顯的抗癌作用。實驗組(50 mg/kg)的相對腫瘤增殖率(T/C)為31.04% (P < 0.05)，同時保持了良好的安全性。
