杂志名称：Bioorganic Chemistry
影响因子：5.1
文章题目：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
作者单位：
上海交通大学药学院
西安交通利物浦大学药学院
引用YOBIBIO产品：
U11-020A 优级胎牛血清 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.

设计并合成了一系列吉尼平衍生物，作为KRAS G12D突变的潜在抑制剂。这些化合物中的大多数对KRAS G12D突变肿瘤细胞(CT26和A427)具有潜在的抗增殖作用。值得注意的是，7种化合物在CT26 (KRAS)和A427 (KRAS)细胞中表现出抗癌作用，IC值在7.06 ~ 9.21μM之间，并有效抑制CT26细胞的集落形成。选择了一种具有代表性的化合物进行生物活性和作用机制的进一步研究。以浓度依赖性方式显著诱导CT26细胞凋亡。此外，提高肿瘤细胞中的活性氧(ROS)水平，并对KRAS信号通路表现出调节作用，从而抑制下游磷酸化蛋白的激活。表面等离子体共振(SPR)实验进一步证实了与KRAS G12D蛋白的结合亲和力，结合K为157μM。在裸鼠肿瘤模型中也有明显的抗癌作用。实验组(50 mg/kg)的相对肿瘤增殖率(T/C)为31.04% (P < 0.05)，同时保持了良好的安全性。