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Updated: Oct 21, 2025
Facile Preparation of 4-Substituted Quinazoline Derivatives
Published on: February 15, 2016
Design, synthesis and biological evaluation of quinazoline derivatives as potent and selective FGFR4 inhibitors
Chenghao Pan1, Wenwen Nie1, Jiao Wang2
1Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
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.
Insights
Researchers developed a new FGFR4 inhibitor, compound 35a, to treat liver cancer. This improved drug candidate shows enhanced stability and potency by blocking the FGF19-FGFR4 pathway, offering a promising therapeutic option.
Area of Science:
- Medicinal Chemistry
- Oncology
- Biochemistry
Background:
- Aberrant fibroblast growth factor 19-fibroblast growth factor receptor 4 (FGF19-FGFR4) signaling drives hepatocellular carcinoma (HCC) proliferation.
- The initial FGFR4 inhibitor, BLU9931, faced challenges due to rapid liver metabolism, hindering clinical progression.
Purpose of the Study:
- To design and synthesize novel quinazoline derivatives targeting FGFR4.
- To improve metabolic stability and maintain or enhance inhibitory activity against FGFR4 compared to BLU9931.
Main Methods:
- Structural modification of BLU9931 in the solvent region pocket.
- In vitro kinase inhibition assays and cellular selectivity assessments.
- Liver microsome stability assays and computational simulations.
Main Results:
- Compound 35a demonstrated potent kinase inhibitory activity (IC50 = 8.5 nM) and cellular selectivity.
- Compound 35a exhibited significantly improved metabolic stability in liver microsomes compared to BLU9931.
- Cellular studies confirmed 35a induces apoptosis by blocking the FGFR4 signaling pathway.
Conclusions:
- Compound 35a represents a promising FGFR4 inhibitor with enhanced metabolic stability and potent anti-cancer activity.
- The structural modifications successfully addressed the metabolic liabilities of previous inhibitors.
- Computational modeling provides insights into the binding interactions driving 35a's efficacy and stability.
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