KRASG12C突变体在近年来已成为一个重要的治疗靶点。共价抑制剂已经在临床上显示了对KRASG12C突变癌症的有希望的抗肿瘤活性。在这项研究中，进行了基于结构和重点化学库分析，导致发现143D作为一种新型，高效和选择性的KRASG12C抑制剂。143D在体内外的抗肿瘤效果可与已知的两种KRASG12C抑制剂AMG510和MRTX849相媲美。在低的纳摩尔浓度下，143D显示了抑制KRASG12C突变的生化和细胞效应的药理效力。143D通过下调KRASG12C依赖的信号转导，选择性地抑制细胞增殖，并诱导G1期细胞周期阻滞和凋亡。与MRTX849相比，143D在组织分布实验中表现出更长的半衰期和更高的最大浓度（Cmax）和面积曲线下的值（AUC），并越过血脑屏障。143D的治疗可以导致KRAS信号通路的持续抑制和KRASG12C突变肿瘤的缩小。此外，143D与EGFR/MEK/ERK信号抑制剂联合治疗在体内外均表现出增强的抗肿瘤活性。综上所述，我们的研究结果表明，143D可能是一种具有良好药理学特性的有前途的药物候选物，可用于治疗KRASG12C突变的癌症。 ©2023年。作者（们），在中国科学院上海药物研究所和中国药理学会的独家许可下。

The KRASG12C mutant has emerged as an important therapeutic target in recent years. Covalent inhibitors have shown promising antitumor activity against KRASG12C-mutant cancers in the clinic. In this study, a structure-based and focused chemical library analysis was performed, which led to the identification of 143D as a novel, highly potent and selective KRASG12C inhibitor. The antitumor efficacy of 143D in vitro and in vivo was comparable with that of AMG510 and of MRTX849, two well-characterized KRASG12C inhibitors. At low nanomolar concentrations, 143D showed biochemical and cellular potency for inhibiting the effects of the KRASG12C mutation. 143D selectively inhibited cell proliferation and induced G1-phase cell cycle arrest and apoptosis by downregulating KRASG12C-dependent signal transduction. Compared with MRTX849, 143D exhibited a longer half-life and higher maximum concentration (Cmax) and area under the curve (AUC) values in mouse models, as determined by tissue distribution assays. Additionally, 143D crossed the blood‒brain barrier. Treatment with 143D led to the sustained inhibition of KRAS signaling and tumor regression in KRASG12C-mutant tumors. Moreover, 143D combined with EGFR/MEK/ERK signaling inhibitors showed enhanced antitumor activity both in vitro and in vivo. Taken together, our findings indicate that 143D may be a promising drug candidate with favorable pharmaceutical properties for the treatment of cancers harboring the KRASG12C mutation.© 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.