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.
Xiaolu Chen  1 ,  Yanan Liu  1 ,  Liting Zhang  1 ,  Daoxing Chen  1 ,  Zhaojun Dong  1 ,  Chengguang Zhao  1 ,  Zhiguo Liu  1 ,  Qinqin Xia  1 ,  Jianzhang Wu  2 ,  Yongheng Chen  3 ,  Xiaohui Zheng  4 ,  Yuepiao Cai  5
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: [email protected].
  • 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: [email protected].
  • 5. School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. Electronic address: [email protected].
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.