Novel third-generation pyrimidines-based EGFR tyrosine kinase inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer

被引：14

作者：

An, Baijiao ^{[1
]}

Liu, Jian ^{[2
,3
]}

Fan, Yangyang ^{[1
]}

Nie, Wenyan ^{[1
]}

Yang, Chunhua ^{[1
]}

Yao, Han ^{[3
]}

Li, Wei ^{[3
]}

Zhang, Yin ^{[1
]}

Li, Xingshu ^{[3
]}

Tian, Geng ^{[1
]}

机构：

[1] Binzhou Med Univ, Shandong Technol Innovat Ctr Mol Targeting & Intel, Yantai 264003, Shandong, Peoples R China

[2] First Med Univ, Hosp Shandong 1, Dept Plast Surg, Jinan 250014, Shandong, Peoples R China

[3] Sun Yat Sen Univ, Sch Pharmaceut Sci, Guangzhou 510006, Peoples R China

来源：

BIOORGANIC CHEMISTRY | 2022年 / 122卷

基金：

中国国家自然科学基金;

关键词：

Non-small-cell lung cancers (NSCLCs); EGFR inhibitors; Signaling pathways; RESISTANCE; THIOPHENE; DESIGN; THIENOPYRIMIDINE; DERIVATIVES; GEFITINIB; APOPTOSIS; ANTITUMOR; RECEPTOR;

D O I：

10.1016/j.bioorg.2022.105743

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：

The critical T790M secondary mutation in epidermal growth-factor receptor (EGFR) mediates resistance to first and second-generation EGFR tyrosine kinase inhibitors. Herein, we identified 12 new 2,4-diaryl pyrimidine derivatives containing thiophene fragments as new selective third-generation EGFR inhibitors. Among them, Compound 6a showed good inhibitory activity against EGFR mutant cells with an IC50 value of 0.0022 +/- 0.001 mu M and was approximately 1730-fold less potent against EGFR WT cells (IC50: 4.499 +/- 0.057 mu M). Moreover, it strongly affected EGFR-mediated signaling pathways, attenuated tumor proliferation via the intrinsic mitochondrial apoptotic pathway, arrested the cell cycle at G0/G1 phase, and induced apoptosis in H1975 cells. It also displayed appropriate pharmacokinetic (PK) parameters with an oral bioavailability value of 33.57%. Additionally, in vivo studies confirmed that 6a suppressed tumor growth in an H1975 xenograft model (25 mg/ kg/d, TGI: 90.24%). Overall, these results suggest that 6a could be a promising lead compound for overcoming the clinical EGFR T790M resistance of patients with non-small-cell lung cancers (NSCLCs).

引用

页数：14

共 32 条

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