2. Academic Validation
  3. Design, synthesis and biological evaluation of imine-containing inhibitors against the triple-mutant EGFR kinases based on the scaffold of osimertinib

Design, synthesis and biological evaluation of imine-containing inhibitors against the triple-mutant EGFR kinases based on the scaffold of osimertinib

  • Bioorg Chem. 2025 Jun 15:160:108474. doi: 10.1016/j.bioorg.2025.108474.
Shi Ding 1,  Yuanyu Wu 2,  Bin Li 2,  Xin Wang 2,  Haotian Ding 2,  Zhenzhen Zhan 2,  Jiwei Shen 1,  Rui Qi 2,  Ziye Gao 2,  Kai Yao 2,  Riya Su 2,  Hanxue Zheng 2,  Zhongyu Tang 2,  Ju Liu 3,  Ye Chen 4
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 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.
  • 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: sy-chenye@163.com.
PMID: 40267777 DOI: 10.1016/j.bioorg.2025.108474
Abstract

A series of EGFR inhibitors were designed and synthesized based on the scaffold of osimertinib, the inhibitory activities against the L858R/T790M/C797S mutant EGFR kinase of which were subsequently evaluated. Compounds with the imine fragments showed the highest kinase inhibitory activity and were proved to be reversible inhibitors, which were represented by the compound DD-8 (IC50 = 0.87 nM). Kinase selectivity assay showed the compounds with imine fragments were preferred to inhibit the triple-mutant EGFR kinases rather than Other subtypes. In the proliferation inhibition assay against the BaF3-EGFR(L858R/T790M/C797S) cell line, compound DD-8 also showed strong inhibitory activity (IC50 = 1.11 μM), and the inhibition rate of which reached 98.8 % at the concentration of 2 μM. To further elucidate the antitumor mechanism of the compound DD-8, a comprehensive series of experiments were conducted, including Apoptosis induction assay, cell cycle arrest assay, western blot assay, cell migration inhibition assay, liver microsomal stability experiment, and molecular docking analysis.

Keywords

Antitumor activity; Cell apoptosis; Molecular docking analysis; Reversible EGFR-TKIs; The L858R/T790M/C797S mutant EGFR kinase.

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