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

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

  • Bioorg Med Chem. 2023 Aug 15;91:117384. doi: 10.1016/j.bmc.2023.117384.
Tingting Jia 1,  Ruoyang Miao 2,  Jiankang Zhang 3,  Huajian Zhu 3,  Chong Zhang 3,  Linghui Zeng 3,  Yanmei Zhao 4,  Weiyan Cheng 5,  Jiaan Shao 6
Affiliations

Affiliations

  • 1 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, China; Department of Pharmacy, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
  • 2 Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
  • 3 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, China.
  • 4 Department of Pharmaceutical Preparation, Hangzhou Xixi Hospital, Hangzhou 310023, China. Electronic address: [email protected].
  • 5 Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address: [email protected].
  • 6 Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Hangzhou City University, Hangzhou 310015, China. Electronic address: [email protected].
PMID: 37356356 DOI: 10.1016/j.bmc.2023.117384
Abstract

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 < 10 nM), indicating its hypoxia-selectivity. A14's high potency may be attributed to its inhibition against multiple kinases, including EGFR, JAK2, ROS1, FLT3, FLT4 and PDGFRα, which was confirmed by binding assays on a panel of 30 kinases. Furthermore, A14 exhibited good bio-reductive property and could bind with nucleophilic Amino acids after being activated under hypoxic conditions. With its anti-proliferative activities and selectivity for hypoxia and oncogenic kinases, A14 shows promise as a multi-target kinase inhibitor for Cancer therapy.

Keywords

EGFR; Hypoxia-activated; Multi-target kinase inhibitor; NSCLC.

Figures
Products