Focal adhesion kinase inhibitors in fibrotic diseases therapy: Development and therapeutic potential

Cailing Gan; Wei Wei; Taixiong Xue; Yuting Xie; Lin Yue; Xingping Su; Yan Yu; Zhihao Liu; Tinghong Ye

doi:10.1016/j.ejmech.2025.117882

Focal adhesion kinase inhibitors in fibrotic diseases therapy: Development and therapeutic potential

Eur J Med Chem. 2025 Jun 18:296:117882. doi: 10.1016/j.ejmech.2025.117882. Online ahead of print.

Authors

Cailing Gan¹, Wei Wei², Taixiong Xue¹, Yuting Xie¹, Lin Yue¹, Xingping Su¹, Yan Yu³, Zhihao Liu⁴, Tinghong Ye⁵

Affiliations

¹ Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
² Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China; Department of Clinical Research, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, 610041, China.
³ Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: 15208432362@163.com.
⁴ Department of Emergency Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China. Electronic address: liuzhihao@scu.edu.cn.
⁵ Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: yeth1309@scu.edu.cn.

PMID: 40570411
DOI: 10.1016/j.ejmech.2025.117882

Abstract

Organ fibrosis, characterized by dysregulated extracellular matrix deposition due to abnormal tissue repair, remains a significant challenge in medical research. Although nintedanib and pirfenidone have been approved for pulmonary fibrosis, effective treatments for hepatic, cardiac, and renal fibrosis remain markedly limited. The focal adhesion kinase (FAK) has been extensively implicated in the pathogenesis of organ fibrosis, with FAK kinase inhibition emerging as a pivotal therapeutic strategy for fibrosis modulation. In this review, we present a comprehensive analysis of FAK's biological functions in fibrotic progression and review preclinical advancements in FAK inhibitor development. We focus on the classification of FAK inhibitors, emphasizing their binding patterns, pharmacodynamic efficacy, and selectivity profiles from the perspective of pharmaceutical chemists. Additionally, we propose strategic frameworks for development of novel drugs targeting FAK for the treatment of fibrosis. The findings discussed in this review can guide the development of FAK inhibitors for treating organ fibrosis and underscore potential challenges in the drug development process.

Keywords: Extracellular matrix; FAK inhibitors; Organ fibrosis; PROTACs; Therapeutic targets.

Publication types

Review