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

Tingting Jia; Ruoyang Miao; Jiankang Zhang; Huajian Zhu; Chong Zhang; Linghui Zeng; Yanmei Zhao; Weiyan Cheng; Jiaan Shao

doi:10.1016/j.bmc.2023.117384

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. Epub 2023 Jun 20.

Authors

Tingting Jia¹, Ruoyang Miao², Jiankang Zhang³, Huajian Zhu³, Chong Zhang³, Linghui Zeng³, Yanmei Zhao⁴, Weiyan Cheng⁵, Jiaan Shao⁶

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: kongjian723@163.com.
⁵ Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address: fccchengwy@zzu.edu.cn.
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: shaoja@zucc.edu.cn.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / chemistry
Cell Line, Tumor
Cell Proliferation
ErbB Receptors
Humans
Hypoxia
Lung Neoplasms* / drug therapy
Nitroimidazoles*
Protein Kinase Inhibitors / chemistry
Protein-Tyrosine Kinases / metabolism
Proto-Oncogene Proteins / metabolism
Structure-Activity Relationship

Substances

osimertinib
Nitroimidazoles
Protein-Tyrosine Kinases
ErbB Receptors
Proto-Oncogene Proteins
Antineoplastic Agents
Protein Kinase Inhibitors