Discovery of novel hypoxia-activated, nitroimidazole constructed multi-target kinase inhibitors on the basis of AZD9291 for the treatment of human lung cancer

• Published in: Bioorganic & medicinal chemistry 2023-08, Vol.91, p.117384-117384, Article 117384
• Main Authors: Jia, Tingting, Miao, Ruoyang, Zhang, Jiankang, Zhu, Huajian, Zhang, Chong, Zeng, Linghui, Zhao, Yanmei, Cheng, Weiyan, Shao, Jiaan
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Cell Line, Tumor; Cell Proliferation; EGFR; ErbB Receptors; Humans; Hypoxia; Hypoxia-activated; Lung Neoplasms - drug therapy; Multi-target kinase inhibitor; Nitroimidazoles; NSCLC; Protein Kinase Inhibitors - chemistry; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Structure-Activity Relationship
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2023.117384

[Display omitted] •A group of hypoxia-activated, nitroimidazole constructed EGFR inhibitors based on AZD9291 were designed.•A14 exhibited significnant anti-proliferative activities and hypoxia-selectivity on H1975 and HCC827 cells.•A14 was potent in inhibiting JAK2, ROS1, FLT3, FLT4 and PDGFRα and was a potential multi-target kinase inhibitor. A group of 4-(1-methyl-1H-indol-3-yl)pyrimidin-2-amine derivatives containing a hypoxia-activated nitroimidazole group were designed as EGFR inhibitors. Among this series, A14 was identified as the optimal compound, exhibiting potent anti-proliferative activities against H1975 and HCC827 cells. Under hypoxic condition, the anti-proliferative activities of A14 improved by 4–6-fold (IC50