设计并合成了一系列京尼平衍生物作为针对 KRAS G12D 突变的潜在抑制剂。这些化合物中的大多数都表现出针对 KRAS G12D 突变肿瘤细胞（CT26 和 A427）的潜在抗增殖作用。值得注意的是，七种化合物在 CT26 (KRASG12D) 和 A427 (KRASG12D) 细胞中表现出抗癌作用，IC50 值范围为 7.06 至 9.21 µM，并有效抑制 CT26 细胞的集落形成。选择一种代表性化合物SK12来进一步研究其生物活性和作用机制。 SK12 以浓度依赖性方式显着诱导 CT26 细胞凋亡。此外，SK12还能提高肿瘤细胞中活性氧（ROS）的水平，并对KRAS信号通路发挥调节作用，从而抑制下游磷酸化蛋白的激活。通过表面等离子共振 (SPR) 测定进一步证实了 SK12 与 KRAS G12D 蛋白的结合亲和力，结合 KD 为 157 µM。 SK12还在裸鼠肿瘤模型中表现出显着的抗癌功效。实验组（50 mg/kg）的相对肿瘤增殖率（T/C）为 31.04%（P < 0.05），同时保持了值得称赞的安全性。版权所有 © 2024 Elsevier Inc. 保留所有权利。

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 IC50 values ranging from 7.06 to 9.21 µM in CT26 (KRASG12D) and A427 (KRASG12D) cells and effectively suppressed the colony formation of CT26 cells. One representative compound SK12 was selected for further investigation into biological activity and action mechanisms. SK12 markedly induced apoptosis in CT26 cells in a concentration-dependent manner. Moreover, SK12 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 SK12 to KRAS G12D protein was further confirmed by the surface plasmon resonance (SPR) assay with a binding KD of 157 µM. SK12 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.Copyright © 2024 Elsevier Inc. All rights reserved.