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

Wei Wei; Zhanzhan Feng; Zhihao Liu; Xinyue Li; Hualong He; Kai Ran; Yaojie Shi; Yongxia Zhu; Tinghong Ye; Chao Gao; Ningyu Wang; Luoting Yu

doi:10.1016/j.ejmech.2021.113978

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. Epub 2021 Nov 11.

Authors

Wei Wei¹, Zhanzhan Feng¹, Zhihao Liu¹, Xinyue Li¹, Hualong He¹, Kai Ran², Yaojie Shi¹, Yongxia Zhu³, Tinghong Ye¹, Chao Gao⁴, Ningyu Wang⁵, Luoting Yu⁶

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: gaochao527@hotmail.com.
⁵ School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, China. Electronic address: wangny-swjtu@swjtu.edu.cn.
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: yuluot@scu.edu.cn.

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.

MeSH terms

Animals
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Dose-Response Relationship, Drug
Drug Design
Drug Screening Assays, Antitumor
Female
Focal Adhesion Kinase 1 / antagonists & inhibitors*
Focal Adhesion Kinase 1 / metabolism
Humans
Indans / chemical synthesis
Indans / chemistry
Indans / pharmacology*
Mice
Mice, Inbred BALB C
Mice, Nude
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Molecular Structure
Neoplasms, Experimental / drug therapy
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Ovarian Neoplasms / drug therapy*
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry
Pyrimidines / pharmacology*
Pyrroles / chemical synthesis
Pyrroles / chemistry
Pyrroles / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Indans
Protein Kinase Inhibitors
Pyrimidines
Pyrroles
Focal Adhesion Kinase 1
PTK2 protein, human