Hu Chen, Wang Aoli, Wu Hong, Qi Ziping, Li Xixiang, Yan Xiao-E, Chen Cheng, Yu Kailin, Zou Fengming, Wang Wenchao, Wang Wei, Wu Jiaxin, Liu Juan, Wang Beilei, Wang Li, Ren Tao, Zhang Shanchun, Yun Cai-Hong, Liu Jing, Liu Qingsong
High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
University of Science and Technology of China, Hefei, Anhui 230036, P. R. China.
Oncotarget. 2017 Mar 14;8(11):18359-18372. doi: 10.18632/oncotarget.15443.
EGFR T790M mutation accounts for about 40-55% drug resistance for the first generation EGFR kinase inhibitors in the NSCLC. Starting from ibrutinib, a highly potent irreversible BTK kinase inhibitor, which was also found to be moderately active to EGFR T790M mutant, we discovered a highly potent irreversible EGFR inhibitor CHMFL-EGFR-26, which is selectively potent against EGFR mutants including L858R, del19, and L858R/T790M. It displayed proper selectivity window between the EGFR mutants and the wide-type. CHMFL-EGFR-26 exhibited good selectivity profile among 468 kinases/mutants tested (S score (1)=0.02). In addition, X-ray crystallography revealed a distinct "DFG-in" and "cHelix-out" inactive binding mode between CHMFL-EGFR-26 and EGFR T790M protein. The compound showed highly potent anti-proliferative efficacy against EGFR mutant but not wide-type NSCLC cell lines through effective inhibition of the EGFR mediated signaling pathway, induction of apoptosis and arresting of cell cycle progression. CHMFL-EGFR-26 bore acceptable pharmacokinetic properties and demonstrated dose-dependent tumor growth suppression in the H1975 (EGFR L858R/T790M) and PC-9 (EGFR del19) inoculated xenograft mouse models. Currently CHMFL-EGFR-26 is undergoing extensive pre-clinical evaluation for the clinical trial purpose.
表皮生长因子受体（EGFR）的T790M突变占非小细胞肺癌（NSCLC）中第一代EGFR激酶抑制剂耐药性的40%-55%。从伊布替尼（一种高效不可逆的布鲁顿酪氨酸激酶（BTK）抑制剂，也被发现对EGFR T790M突变体有中等活性）开始，我们发现了一种高效不可逆的EGFR抑制剂CHMFL-EGFR-26，它对包括L858R、del19和L858R/T790M在内的EGFR突变体具有选择性强效作用。它在EGFR突变体和野生型之间显示出合适的选择性窗口。CHMFL-EGFR-26在468种测试的激酶/突变体中表现出良好的选择性特征（S评分(1)=0.02）。此外，X射线晶体学揭示了CHMFL-EGFR-26与EGFR T790M蛋白之间独特的“DFG-in”和“c螺旋-out”无活性结合模式。该化合物通过有效抑制EGFR介导的信号通路、诱导细胞凋亡和阻止细胞周期进程，对EGFR突变体而非野生型NSCLC细胞系显示出高效的抗增殖功效。CHMFL-EGFR-26具有可接受的药代动力学性质，并在接种了H1975（EGFR L858R/T790M）和PC-9（EGFR del19）的异种移植小鼠模型中显示出剂量依赖性的肿瘤生长抑制作用。目前，CHMFL-EGFR-26正在为临床试验目的进行广泛的临床前评估。
