KRAS is the most commonly altered oncogene of the RAS family, especially the G12C mutant (KRAS^G12C), which has been a promising drug target for many cancers. On the basis of the bicyclic pyridopyrimidinone framework of the first-in-class clinical KRAS^G12C inhibitor AMG510, a scaffold hopping strategy was conducted including a F-OH cyclization approach and a pyridinyl N-atom working approach leading to new tetracyclic and bicyclic analogues. Compound 26a was identified possessing binding potency of 1.87 μM against KRAS^G12C and cell growth inhibition of 0.79 μM in MIA PaCa-2 pancreatic cancer cells. Treatment of 26a with NCI-H358 cells resulted in down-regulation of KRAS-GTP levels and reduction of phosphorylation of downstream ERK and AKT dose-dependently. Molecular docking suggested that the fluorophenol moiety of 26a occupies a hydrophobic pocket region thus forming hydrogen bonding to Arg68. These results will be useful to guide further structural modification.

KRAS是RAS家族中最常见的致癌基因，尤其是G12C突变体（KRAS ^G12C），它已成为许多癌症的有希望的药物靶标。基于一流的临床KRAS ^G12C抑制剂AMG510的双环吡啶并嘧啶酮框架，进行了支架跳跃策略，包括F-OH环化方法和吡啶基N原子工作方法，从而产生了新的四环和双环类似物。鉴定出在MIA PaCa-2胰腺癌细胞中具有对KRAS ^G12C的结合效力为^1.87μM并且对细胞生长的抑制为^0.79μM的化合物26a。26a的治疗NCI-H358细胞诱导的KRAS-GTP水平下调，下游ERK和AKT磷酸化的剂量依赖性降低。分子对接表明26a的氟苯酚部分占据疏水口袋区，从而形成与Arg68的氢键。这些结果将有助于指导进一步的结构修饰。