Novel Dual-Target Kinase Inhibitors of EGFR and ALK Were Designed, Synthesized, and Induced Cell Apoptosis in Non-Small Cell Lung Cancer

被引：11

作者：

Fan, Yangyang ^{[1
]}

Li, Wei ^{[2
]}

Nie, Wenyan ^{[1
]}

Yao, Han ^{[2
]}

Ren, Yuanyuan ^{[2
]}

Wang, Mengxuan ^{[1
]}

Nie, Haoran ^{[1
]}

Gu, Chenxi ^{[2
]}

Liu, Jiadai ^{[2
]}

An, Baijiao ^{[1
,3
]}

机构：

[1] Binzhou Med Univ, Sch Pharm, Yantai 264003, Peoples R China

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

[3] Shandong Technol Innovat Ctr Mol Targeting & Intel, Yantai 264003, Peoples R China

来源：

MOLECULES | 2023年 / 28卷 / 05期

关键词：

non-small-cell lung cancer (NSCLC); EGFR; ALK; kinase inhibitor; therapeutic strategy; ANAPLASTIC LYMPHOMA KINASE; RESISTANCE; DISCOVERY; MUTATION; THERAPY; T790M;

D O I：

10.3390/molecules28052006

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：

ALK-positive NSCLC coexisting with EGFR mutations is a frequently occurring clinical phenomenon. Targeting ALK and EGFR simultaneously may be an effective way to treat these cancer patients. In this study, we designed and synthesized ten new dual-target EGFR/ALK inhibitors. Among them, the optimal compound 9j exhibited good activity with IC50 values of 0.07829 +/- 0.03 mu M and 0.08183 +/- 0.02 mu M against H1975 (EGFR (T790M/L858R)) and H2228 (EML4-ALK) cells, respectively. Immunofluorescence assays indicated that the compound could simultaneously inhibit the expression of phosphorylated EGFR and ALK proteins. A kinase assay demonstrated that compound 9j could inhibit both EGFR and ALK kinases; thus, exerting an antitumor effect. Additionally, compound 9j induced apoptosis in a dose-dependent manner and inhibited the invasion and migration of tumor cells. All of these results indicate that 9j is worthy of further study.

引用

页数：16

共 37 条

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