Design, synthesis and biological evaluation of 7-((7H-pyrrolo[2,3-d] pyrimidin-4-yl)oxy)-2,3-dihydro-1H-inden-1-one derivatives as potent FAK inhibitors for the treatment of ovarian cancer

被引：13

作者：

Wei, Wei ^{[1
]}

Feng, Zhanzhan ^{[1
]}

Liu, Zhihao ^{[1
]}

Li, Xinyue ^{[1
]}

He, Hualong ^{[1
]}

Ran, Kai ^{[2
]}

Shi, Yaojie ^{[1
]}

Zhu, Yongxia ^{[3
]}

Ye, Tinghong ^{[1
]}

Gao, Chao ^{[4
,5
]}

Wang, Ningyu ^{[6
]}

Yu, Luoting ^{[1
]}

机构：

[1] Sichuan Univ, Sichuan Univ Univ Oxford Huaxi Joint Ctr Gastroin, West China Hosp,Lab Emergency Med, Dept Emergency Med,State Key Lab Biotherapy & Can, Chengdu 610041, Peoples R China

[2] Chongqing Univ Arts & Sci, Coll Pharm, Natl & Local Joint Engn Res Ctr Targeted & Innova, Chongqing Key Lab Kinase Modulators Innovat Med, Chongqing 402160, Peoples R China

[3] Univ Elect Sci & Technol China, Dept Clin Pharm, Sichuan Canc Hosp & Inst, Sichuan Canc Ctr,Sch Med, Chengdu 610041, Peoples R China

[4] Sichuan Univ, West China Hosp, Lab Human Dis & Immunotherapies, Chengdu 610041, Peoples R China

[5] Sichuan Univ, Inst Immunol & Inflammat, Frontiers Sci Ctr Dis Related Mol Network, West China Hosp, Chengdu 610041, Peoples R China

[6] Southwest Jiaotong Univ, Sch Life Sci & Engn, Chengdu 610031, Peoples R China

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 228卷

基金：

中国国家自然科学基金;

关键词：

FAK; Kinase inhibitor; Structure-activity relationship; Ovarian cancer; Anti-Tumor; FOCAL ADHESION KINASE; CELL MOTILITY; NUCLEAR FAK; PHASE-I; THERAPY; GROWTH;

D O I：

10.1016/j.ejmech.2021.113978

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Focal adhesion kinase (FAK) promotes tumor progression by intracellular signal transduction and regulation of gene expression and protein turnover, which is a compelling therapeutic target for various cancer types, including ovarian cancer. However, the clinical responses of FAK inhibitors remain unsatisfactory. Here, we describe the discovery of FAK inhibitors using a scaffold hopping strategy. Structure-activity relationship (SAR) exploration identified 36 as a potent FAK inhibitor, which exhibited inhibitory activities against FAK signaling in vitro. Treatment with 36 not only decreased migration and invasion of PA-1 cells, but also reduced expression of MMP-2 and MMP-9. Moreover, 36 inhibited tumor growth and metastasis, and no obvious adverse effects were observed during the in vivo study. These results revealed the potential of FAK inhibitor 36 for treatment of ovarian cancer. (C) 2021 Elsevier Masson SAS. All rights reserved.

引用

页数：23

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