143d，一种新型的选择性KRASG12C抑制剂在临床前模型中表现出有效的抗肿瘤活性
143D, a novel selective KRASG12C inhibitor exhibits potent antitumor activity in preclinical models
影响因子:8.40000
分区:医学2区 / 药学1区 化学：综合2区
发表日期:2023 Jul
作者:
Lan-Song Xu, Su-Xin Zheng, Liang-He Mei, Ke-Xin Yang, Ya-Fang Wang, Qiang Zhou, Xiang-Tai Kong, Ming-Yue Zheng, Hua-Liang Jiang, Cheng-Ying Xie
摘要
近年来，KRASG12C突变体已成为重要的治疗靶点。共价抑制剂已显示出对诊所中KRASG12C突变癌的有希望的抗肿瘤活性。在这项研究中，进行了基于结构和集中的化学文库分析，这导致143d鉴定为一种新型，有效和选择性的KRASG12C抑制剂。 143d体外和体内的抗肿瘤功效与AMG510和MRTX849的抗肿瘤功效相当，这是两个良好的KRASG12C抑制剂。在低纳摩尔浓度下，143D显示出抑制KRASG12C突变作用的生化和细胞效力。 143d通过下调KRASG12C依赖性信号转导，选择性抑制细胞增殖和诱导G1相细胞周期停滞和凋亡。与MRTX849相比，143D在小鼠模型中表现出更长的半衰期和更高的最大浓度（CMAX）和曲线（AUC）值的面积，如组织分布测定所确定。另外，143d越过了血脑屏障。用143D治疗导致KRASG12C突变肿瘤中KRAS信号传导和肿瘤消退的持续抑制作用。此外，143D与EGFR/MEK/ERK信号抑制剂结合使用，在体外和体内表现出增强的抗肿瘤活性。综上所述，我们的发现表明，143D可能是有前途的候选药物，具有有利的药物特性，用于治疗携带Krasg12c突变的癌症。
Abstract
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.