2. Academic Validation
  3. Design, synthesis and biological evaluation of novel N-(3-amino-4-methoxyphenyl)acrylamide derivatives as selective EGFRL858R/T790M kinase inhibitors

Design, synthesis and biological evaluation of novel N-(3-amino-4-methoxyphenyl)acrylamide derivatives as selective EGFRL858R/T790M kinase inhibitors

  • Bioorg Chem. 2022 Jan;118:105471. doi: 10.1016/j.bioorg.2021.105471.
Shi Ding 1,  Xiaoyong Dong 2,  Ziye Gao 2,  Xiangshan Zheng 2,  Jingchao Ji 2,  Mingjuan Zhang 2,  Fang Liu 2,  Shuang Wu 2,  Min Li 2,  Wenshan Song 2,  Jiwei Shen 1,  Wenwen Duan 3,  Ju Liu 4,  Ye Chen 5
Affiliations

Affiliations

  • 1 College of Pharmacy of Liaoning University, 66 Chongshan Road, Huanggu District, Shenyang 110036, PR China; API Engineering Technology Research Center of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang 110036, PR China; Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang 110036, PR China.
  • 2 College of Pharmacy of Liaoning University, 66 Chongshan Road, Huanggu District, Shenyang 110036, PR China.
  • 3 iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Pudong District, Shanghai 201210, PR China.
  • 4 College of Pharmacy of Liaoning University, 66 Chongshan Road, Huanggu District, Shenyang 110036, PR China; API Engineering Technology Research Center of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang 110036, PR China; Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang 110036, PR China. Electronic address: liuju1216@126.com.
  • 5 College of Pharmacy of Liaoning University, 66 Chongshan Road, Huanggu District, Shenyang 110036, PR China; API Engineering Technology Research Center of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang 110036, PR China; Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang 110036, PR China. Electronic address: sy-chenye@163.com.
PMID: 34798457 DOI: 10.1016/j.bioorg.2021.105471
Abstract

On the basis of N-(3-amino-4-methoxyphenyl)acrylamide scaffold, a series of novel compounds containing 3-substitutional-1-methyl-1H-indole, 2-substitutional pyrrole or thiophene moieties were synthesized and their in vitro antiproliferation activities against A549 and H1975 cell lines were evaluated. The results indicated that most of the compounds showed moderate to excellent antitumor activities. Especially, compounds 9a (A549 IC50 = 1.96 μM, H1975 IC50 = 0.095 μM), 17i (A549 IC50 = 4.17 μM, H1975 IC50 = 0.052 μM), 17j (A549 IC50 = 1.67 μM, H1975 IC50 = 0.061 μM) exhibited comparable antitumor activities and selectivity ratios compared to the positive control osimertinib (A549 IC50 = 2.91 μM, H1975 IC50 = 0.064 μM). In vitro inhibitory activities against EGFR kinases containing different mutations were also tested. Compound 17i showed remarkable inhibitory activity (with IC50 value of 1.7 nM) to EGFRL858R/T790M kinase and selectivity (22-folds compared to EGFRWT kinase). Furthermore, acridine orange/ethidium bromide (AO/EB) staining assay, cell Apoptosis assay, cell cycle distribution assay and wound-healing assay of the compounds 9a and 17i were performed on H1975 cell line. The results showed dose-dependent activities of the induction of Apoptosis, G0/G1-phase arrestation and inhibition of migration, which were similar to the positive control osimertinib. Additionally, molecular docking analysis was performed to seek the possible binding mode between the selected compounds (9a, 17i-17j) and EGFRL858R/T790M kinase. The results demonstrated that compound 17i is a promising candidate and worth further study.

Keywords

Antitumor activity; Docking study; EGFR-TKIs; Kinase selectivity; N-(3-amino-4-methoxyphenyl)acrylamide derivatives.

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