2. Academic Validation
  3. Discovery and structural optimization of potent epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M/C797S resistance mutation for lung cancer treatment

Discovery and structural optimization of potent epidermal growth factor receptor (EGFR) inhibitors against L858R/T790M/C797S resistance mutation for lung cancer treatment

  • Eur J Med Chem. 2022 Jul 5;237:114381. doi: 10.1016/j.ejmech.2022.114381.
Cheng Wang 1,  Xin Wang 2,  Zhi Huang 2,  Tianqi Wang 2,  Yongwei Nie 2,  Shengyong Yang 3,  Rong Xiang 4,  Yan Fan 5
Affiliations

Affiliations

  • 1 School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China; Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, China.
  • 2 School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
  • 3 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China.
  • 4 School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China; 2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin, 300071, China. Electronic address: rxiang@nankai.edu.cn.
  • 5 School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China; 2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin, 300071, China. Electronic address: yanfan@nankai.edu.cn.
PMID: 35447433 DOI: 10.1016/j.ejmech.2022.114381
Abstract

The C797S mutation in EGFR is a leading mechanism of clinically acquired resistance against osimertinib for non-small cell lung Cancer (NSCLC). In this study, we identified a potent and oral EGFRL858R/T790M/C797S tyrosine kinase inhibitor, 14aj with a novel chemical scaffold. Compound 14aj showed low nanomolar activity against EGFRL858R/T790M/C797S mutant with IC50 value as 0.010 μM. In vitro assays, compound 14aj exhibited high potency against NSCLC cells harboring EGFRL858R/T790M/C797S and induced tumor cell cycle arrest and cell Apoptosis. 14aj inhibited cellular phosphorylation of EGFR. In vivo xenograft mouse model, oral administration of compound 14aj led to significant tumor regression without obvious toxicity. In addition, this compound showed good pharmacokinetics.

Keywords

C797S; EGFR; Inhibitor; NSCLC.

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