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Design, synthesis, and antitumor activity evaluation of potent fourth-generation EGFR inhibitors for treatment of Osimertinib resistant non-small cell lung cancer (NSCLC).

Abstract
Epidermal growth factor receptor (EGFR) is one of the most studied drug targets for treating non-small-cell lung cancer (NSCLC). However, there are no approved inhibitors for the C797S resistance mutation caused by the third-generation EGFR inhibitor (Osimertinib). Therefore, the development of fourth-generation EGFR inhibitors is urgent. In this study, we clarified the structure-activity relationship of several synthesized compounds as fourth-generation inhibitors against human triple (Del19/T790M/C797S) mutation. Representative compound 52 showed potent inhibitory activity against EGFRL858R/T790M/C797S with an IC50 of 0.55 nM and significantly inhibited the proliferation of the Ba/F3 cell line harboring EGFRL858R/T790M/C797S with an IC50 of 43.28 nM. Moreover, 52 demonstrated good pharmacokinetic properties and excellent in vivo efficacy. Overall, the compound 52 can be considered a promising candidate for overcoming EGFR C797S-mediated mutations.
AuthorsYuchen Zhang, Lexian Tong, Fangjie Yan, Ping Huang, Cheng-Liang Zhu, Chenghao Pan
JournalBioorganic chemistry (Bioorg Chem) Vol. 147 Pg. 107394 (Jun 2024) ISSN: 1090-2120 [Electronic] United States
PMID38691906 (Publication Type: Journal Article)
CopyrightCopyright © 2024 Elsevier Inc. All rights reserved.
Chemical References
  • osimertinib
  • EGFR protein, human
Topics
  • ErbB Receptors (antagonists & inhibitors, metabolism, genetics)
  • Humans
  • Carcinoma, Non-Small-Cell Lung (drug therapy, pathology)
  • Antineoplastic Agents (pharmacology, chemistry, chemical synthesis)
  • Lung Neoplasms (drug therapy, pathology)
  • Acrylamides (pharmacology, chemistry, chemical synthesis)
  • Structure-Activity Relationship
  • Protein Kinase Inhibitors (pharmacology, chemistry, chemical synthesis)
  • Aniline Compounds (pharmacology, chemistry, chemical synthesis, therapeutic use)
  • Cell Proliferation (drug effects)
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Drug Resistance, Neoplasm (drug effects)
  • Molecular Structure
  • Dose-Response Relationship, Drug
  • Animals
  • Mice
  • Cell Line, Tumor
  • Mutation
  • Indoles
  • Pyrimidines

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