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.
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Authors | Yuchen Zhang, Lexian Tong, Fangjie Yan, Ping Huang, Cheng-Liang Zhu, Chenghao Pan |
Journal | Bioorganic chemistry
(Bioorg Chem)
Vol. 147
Pg. 107394
(Jun 2024)
ISSN: 1090-2120 [Electronic] United States |
PMID | 38691906
(Publication Type: Journal Article)
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Copyright | Copyright © 2024 Elsevier Inc. All rights reserved. |
Chemical References |
- osimertinib
- EGFR protein, human
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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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