2. Academic Validation
  3. Design, synthesis, and biological evaluation of quinazoline derivatives with covalent reversible warheads as potential FGFR4 inhibitors

Design, synthesis, and biological evaluation of quinazoline derivatives with covalent reversible warheads as potential FGFR4 inhibitors

  • Bioorg Chem. 2022 Apr;121:105673. doi: 10.1016/j.bioorg.2022.105673.
Wenwen Nie 1,  Yang Lu 1,  Chenghao Pan 1,  Jian Gao 1,  Mengxin Luo 1,  Jiaming Du 1,  Jiao Wang 1,  Peihua Luo 2,  Hong Zhu 1,  Jinxin Che 3,  Qiaojun He 4,  Xiaowu Dong 5
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 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China. Electronic address: chejx@zju.edu.cn.
  • 4 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.
  • 5 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: 35217375 DOI: 10.1016/j.bioorg.2022.105673
Abstract

Fibroblast Growth Factor receptor 4 (FGFR4) together with co-receptors modulate the activation of downstream proteins that regulate fundamental processes, and elevated FGFR4 activity is associated with Hepatocellular Carcinoma (HCC). Hence, FGFR4 is a promising therapeutic target for HCC. Based on BLU9931, we designed and synthesized a series of phenylquinazoline derivatives as novel inhibitors of FGFR4 through the covalent reversible strategy. Among them, a novel compound (C3) showed FGFR4 and cell proliferation inhibitory activity. Cellular mechanism studies demonstrated that compound C3 induced Apoptosis via the FGFR4 signaling pathway blockage. Further mechanism study showed that C3 has the reversible covalent binding capacity, could be used as a reference for the development of novel FGFR4 covalent reversible inhibitors.

Keywords

Anti-tumor; Covalent reversible; FGFR4 inhibitor.

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