Design, synthesis, and biological evaluation of indazole derivatives as selective and potent FGFR4 inhibitors for the treatment of FGF19-driven hepatocellular cancer

Xiaolu Chen; Yanan Liu; Liting Zhang; Daoxing Chen; Zhaojun Dong; Chengguang Zhao; Zhiguo Liu; Qinqin Xia; Jianzhang Wu; Yongheng Chen; Xiaohui Zheng; Yuepiao Cai

doi:10.1016/j.ejmech.2021.113219

Design, synthesis, and biological evaluation of indazole derivatives as selective and potent FGFR4 inhibitors for the treatment of FGF19-driven hepatocellular cancer

Eur J Med Chem. 2021 Mar 15:214:113219. doi: 10.1016/j.ejmech.2021.113219. Epub 2021 Jan 29.

Authors

Affiliations

¹ School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
² School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: wjzwzmu@163.com.
³ Department of Oncology, NHC Key Laboratory of Cancer Proteomics and Laboratory of Structural Biology, Key Laboratory of Medical Genetics and College of Life Science, and National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
⁴ School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: zhengxh@wmu.edu.cn.
⁵ School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: ypcai@wmu.edu.cn.

PMID: 33618175
DOI: 10.1016/j.ejmech.2021.113219

Abstract

Fibroblast growth factor receptor 4 (FGFR4) is a member of the fibroblast growth factor receptor family, which is closely related to the occurrence and development of hepatocellular carcinoma (HCC). In this article, a series of indazole derivatives were designed and synthesized by using computer-aided drug design (CADD) and structure-based design strategies, and then they were evaluated for their inhibition of FGFR4 kinase and antitumor activity. F-30 was subtly selective for FGFR4 compared to FGFR1; it affected cell growth and migration by inhibiting FGFR4 pathways in HCC cell lines in a dose-dependent manner.

Keywords: Antitumor activity; Covalent inhibitor; Fibroblast growth factor receptor 4; Hepatocellular carcinoma; Indazole derivatives.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Indazoles / chemical synthesis
Indazoles / chemistry
Indazoles / pharmacology*
Liver Neoplasms / drug therapy*
Liver Neoplasms / metabolism
Liver Neoplasms / pathology
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Receptor, Fibroblast Growth Factor, Type 4
Structure-Activity Relationship

Substances

Antineoplastic Agents
Indazoles
Protein Kinase Inhibitors
FGFR4 protein, human
Receptor, Fibroblast Growth Factor, Type 4