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Design, synthesis and biological evaluation of novel tumor hypoxia-activated EGFR tyrosine kinase inhibitors

Authors :
Tingting, Jia
Ruoyang, Miao
Jiaohua, Lin
Chong, Zhang
Linghui, Zeng
Jiankang, Zhang
Jiaan, Shao
Zongfu, Pan
Haiping, Wang
Huajian, Zhu
Weiyan, Cheng
Source :
Bioorganic Chemistry. 129:106138
Publication Year :
2022
Publisher :
Elsevier BV, 2022.

Abstract

Hypoxia is widespread in solid tumors, such as NSCLC, and has become a very attractive target. On the basis of AZD9291 scaffold, novel hypoxia-targeted EGFR inhibitors without the acrylamide warhead but containing hypoxic reductive activation groups were described. Among them, compound JT21 exhibited impressive inhibitory activity (ICsub50/sub = 23 nM) against EGFRsupL858R/T790M/supand displayed about 21-fold inhibitory activity decrease against EGFRsupwt/sup. Under hypoxia, JT21 exhibited more significant proliferation inhibitory activities against H1975 cells (ICsub50/sub = 7.39 ± 2.20 nM) and HCC827 cells (ICsub50/sub = 5.88 ± 0.85 nM) than that of AZD9291, which was about 5 times more effective than normoxia activities. Meanwhile, the weak inhibition effects on A549 and BEAS-2B cells suggested JT21 might be a selective inhibitor for EGFR mutations with low toxicity. Furthermore, JT21 could induce apoptosis of H1975 cells under hypoxia and showed good bio-reductive property.

Details

ISSN :
00452068
Volume :
129
Database :
OpenAIRE
Journal :
Bioorganic Chemistry
Accession number :
edsair.doi.dedup.....380464d9e578979f5cd9a4a1b16f908f
Full Text :
https://doi.org/10.1016/j.bioorg.2022.106138