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

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.

• Authors: Cheng Wang, Xin Wang, Zhi Huang, Tianqi Wang, Yongwei Nie, Shengyong Yang, Rong Xiang, Yan Fan
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 237 Pg. 114381 (Jul 05 2022) ISSN: 1768-3254 [Electronic] France
• PMID: 35447433 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• EGFR protein, human
• ErbB Receptors

Topics

• Animals
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• ErbB Receptors
• Humans
• Lung Neoplasms (drug therapy, genetics, pathology)
• Mice
• Mutation
• Protein Kinase Inhibitors (chemistry)