2. Academic Validation
  3. Design, synthesis and biological evaluation of quinazoline derivatives as potent and selective FGFR4 inhibitors

Design, synthesis and biological evaluation of quinazoline derivatives as potent and selective FGFR4 inhibitors

  • Eur J Med Chem. 2021 Dec 5:225:113794. doi: 10.1016/j.ejmech.2021.113794.
Chenghao Pan 1,  Wenwen Nie 1,  Jiao Wang 2,  Jiamin Du 2,  Zhichao Pan 1,  Jian Gao 1,  Yang Lu 1,  Jinxin Che 1,  Hong Zhu 2,  Haibin Dai 3,  Binhui Chen 4,  Qiaojun He 5,  Xiaowu Dong 6
Affiliations

Affiliations

  • 1 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 2 Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 3 Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 4 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: achenbinhui@hotmail.com.
  • 5 Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, PR China. Electronic address: qiaojunhe@zju.edu.cn.
  • 6 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, PR China; Cancer Center, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: dongxw@zju.edu.cn.
PMID: 34488024 DOI: 10.1016/j.ejmech.2021.113794
Abstract

Aberrant activation of the Fibroblast Growth Factor 19-fibroblast growth factor receptor 4 (FGF19-FGFR4) signaling pathway has been proved to promote hepatocellular carcinoma (HCC) proliferation. It is assumed that the first FGFR4 Inhibitor BLU9931 did not enter clinical studies, presumably due to its rapid metabolism in liver microsomes. Here, we report the development of series of quinazoline derivatives based on FGFR4 Inhibitor BLU9931 through structural modification of its solvent region pocket to minimize its potential metabolic liability. Among them, compound 35a exhibited comparable or superior kinase inhibitory activity (IC50 = 8.5 nM) and selectivity in cells. More importantly, compound 35a improved liver microsomes stability compared to BLU9931. Cellular mechanistic studies demonstrated that 35a induced Apoptosis via the FGFR4 signaling pathway blockage. In addition, the computational simulation revealed the possible binding mode to FGFR4 protein, which provides a plausible explanation of high potent and metabolic stability.

Keywords

FGFR4 inhibitors; Hepatocellular carcinoma (HCC); Solvent region modification.

Figures