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

Chenghao Pan; Wenwen Nie; Jiao Wang; Jiamin Du; Zhichao Pan; Jian Gao; Yang Lu; Jinxin Che; Hong Zhu; Haibin Dai; Binhui Chen; Qiaojun He; Xiaowu Dong

doi:10.1016/j.ejmech.2021.113794

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. Epub 2021 Aug 19.

Authors

Chenghao Pan¹, Wenwen Nie¹, Jiao Wang², Jiamin Du², Zhichao Pan¹, Jian Gao¹, Yang Lu¹, Jinxin Che¹, Hong Zhu², Haibin Dai³, Binhui Chen⁴, Qiaojun He⁵, Xiaowu Dong⁶

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Line, Tumor
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
Microsomes, Liver / chemistry
Microsomes, Liver / metabolism
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology*
Receptor, Fibroblast Growth Factor, Type 4 / antagonists & inhibitors*
Receptor, Fibroblast Growth Factor, Type 4 / metabolism
Structure-Activity Relationship

Substances

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