使用新的二氢喹喔啉酮衍生物探索EGFRL858R/T790M酪氨酸激酶抑制剂，用于处理非小细胞肺癌。
Exploration of novel dihydroquinoxalinone derivatives as EGFRL858R/T790M tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer.
发表日期：2023 Mar 27
作者：
Yu Cao, Xixuan Lu, Liping Fu, Tao Shi, Chong Zhang, Linghui Zeng, Jiankang Zhang, Jiaan Shao, Jianjun Xi, Zongfu Pan, Shourong Liu, Huajian Zhu
来源：
BIOORGANIC CHEMISTRY
摘要：
为了克服第一代表皮生长因子受体（EGFR）激酶抑制剂的药物耐受性和第二代抑制剂介导的非选择性毒性，利用剪接原理设计和合成了一系列含二氢喹噁啉酮（8-30）的Osimertinib衍生物作为新型EGFR双突变体L858R/T790M的第三代抑制剂。其中，化合物29表现出出色的对EGFRL858R/T790M激酶抑制活性，IC50值为0.55±0.02 nM，并在H1975细胞上表现出强效的抗增殖活性，其IC50值为5.88±0.07 nM。此外，对H1975细胞EGFR介导的信号途径的强烈下调效应以及促进凋亡的作用证实了其强效的抗肿瘤活性。在各种体外实验中，化合物29也被证明具有良好的ADME特性。进一步的体内研究证实，化合物29可以抑制异种移植瘤的生长。这些结果证实化合物29是一个有前途的基础化合物，用于针对耐药性EGFR突变的靶向药物。Copyright © 2023 Elsevier Inc. All rights reserved.
To overcome or delay the drug-resistance of first-generation epidermal growth factor receptor (EGFR) kinase inhibitors and non-selectivity toxicity mediated by second-generation inhibitors, splicing principle was employed to design and synthesize a series of Osimertinib derivatives containing dihydroquinoxalinone (8-30) as the novel third-generation inhibitors against double mutant L858R/T790M in EGFR. Among them, compound 29 showed excellent kinase inhibitory activity against EGFRL858R/T790M with an IC50 value of 0.55 ± 0.02 nM and potent anti-proliferative activity against H1975 cells with an IC50 value of 5.88 ± 0.07 nM. Moreover, the strong down-regulation effect of EGFR-mediated signaling pathways and the promotion of apoptosis in H1975 cells confirmed its potent antitumor activities. Compound 29 was also demonstrated with good ADME profile in various in vitro assays. Further in vivo studies confirmed that compound 29 could suppress the growth of xenograft tumors. These results verified that compound 29 would be a promising lead compound for targeting drug-resistant EGFR mutations.Copyright © 2023 Elsevier Inc. All rights reserved.