KRASG12C 抑制剂药物开发的突破为靶向替代 KRAS 突变（尤其是最常见的 KRASG12D 突变）提供了灵感。基于 MRTX1133 与 KRASG12D 复合物的结构分析，进行了全面的结构活性研究，发现了几种化合物（22、28 和 31），它们在抑制 KRASG12D 依赖性克隆生长方面表现出更高的效力癌细胞。这些新化合物显着且选择性地抑制 RBD 肽与 GTP 结合的 KRASG12D 的结合，IC50 值在 0.48 至 1.21 nM 之间。这些新型抑制剂被发现在 AsPC-1 异种移植小鼠模型中具有剂量依赖性抗肿瘤功效，每天两次（腹腔注射）20 mg/kg 剂量时，肿瘤生长抑制率约为 70%。尽管与 MRTX1133 相似的非最佳药代动力学特性，这些新抑制剂在体外和体内的高效力仍需要进一步分析。

The breakthrough in drug development of KRASG12C inhibitors provides inspiration for targeting alternative KRAS mutations, especially the most prevalent KRASG12D variant. Based on the structural analysis of MRTX1133 in complex with KRASG12D, a comprehensive structure-activity study was conducted, which led to the discovery of several compounds (22, 28, and 31) that showed higher potency in suppressing the clonogenic growth of KRASG12D-dependent cancer cells. These new compounds markedly and selectively inhibited the binding of RBD peptide to GTP-bound KRASG12D with IC50 values between 0.48 and 1.21 nM. These new inhibitors were found to have dose-dependent anti-tumor efficacy in the AsPC-1 xenograft mouse models with a tumor growth inhibition of approximately 70% at a dose of 20 mg/kg twice daily (i.p.). Despite the non-optimal pharmacokinetic properties similar to those of MRTX1133, the high in vitro and in vivo potency of these new inhibitors call for further profiling.