2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2022 Jan 15;228:113978. doi: 10.1016/j.ejmech.2021.113978.
Wei Wei 1,  Zhanzhan Feng 1,  Zhihao Liu 1,  Xinyue Li 1,  Hualong He 1,  Kai Ran 2,  Yaojie Shi 1,  Yongxia Zhu 3,  Tinghong Ye 1,  Chao Gao 4,  Ningyu Wang 5,  Luoting Yu 6
Affiliations

Affiliations

  • 1 Laboratory of Emergency Medicine, Department of Emergency Medicine, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
  • 2 College of Pharmacy, National & Local Joint Engineering Research Center of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, Chongqing University of Arts and Sciences, Chongqing, 402160, China.
  • 3 Department of Clinical Pharmacy, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, China.
  • 4 Laboratory of Human Diseases and Immunotherapies, West China Hospital, Sichuan University, Chengdu, 610041, China; Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
  • 5 School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China. Electronic address: [email protected].
  • 6 Laboratory of Emergency Medicine, Department of Emergency Medicine, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 34810020 DOI: 10.1016/j.ejmech.2021.113978
Abstract

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.

Keywords

Anti-Tumor; FAK; Kinase inhibitor; Ovarian cancer; Structure-activity relationship.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-143407
    FAK Inhibitor
    FAK