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

被引：6

作者：

Zhang, Yuchen ^{[1
,2
]}

Tong, Lexian ^{[2
]}

Yan, Fangjie ^{[2
]}

Huang, Ping ^{[3
,4
,5
]}

Zhu, Cheng-Liang ^{[1
,2
]}

Pan, Chenghao ^{[1
,2
]}

机构：

[1] Zhejiang Univ, Inst Pharmacol & Toxicol, Coll Pharmaceut Sci, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou 310058, Peoples R China

[2] Zhejiang Univ, Innovat Inst Artificial Intelligence Med, Hangzhou 310018, Peoples R China

[3] Hangzhou Med Coll, Zhejiang Prov Peoples Hosp,Affiliated Peoples Hos, Dept Pharm, Ctr Clin Pharm,Canc Ctr, Hangzhou, Zhejiang, Peoples R China

[4] Key Lab Endocrine Gland Dis Zhejiang Prov, Hangzhou, Peoples R China

[5] Zhejiang Prov Clin Res Ctr Malignant Tumor, Hangzhou 310014, Zhejiang, Peoples R China

来源：

BIOORGANIC CHEMISTRY | 2024年 / 147卷

基金：

中国国家自然科学基金;

关键词：

NSCLC; EGFR; Structure-activity relationship; Triple mutation; DISCOVERY;

D O I：

10.1016/j.bioorg.2024.107394

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 EGFR(L858R/T790M/C797S) with an IC50 of 0.55 nM and significantly inhibited the proliferation of the Ba/F3 cell line harboring EGFR(L858R/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.

引用

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