Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 26, Issue 16, Pages 4735-4744Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2018.08.013
Keywords
Multi-target inhibitors; Receptor tyrosine kinase; FLT3; KDR; PDGFR-beta; Antiangiogenes
Funding
- National Natural Science Foundation of China [81302634, 21302225]
- China Scholarship Council [201407060046]
- Natural Science Foundation of Jiangsu Province [BK20151563, BK20130662]
- Six Talents Project Funded by Jiangsu Province [2013-YY-010]
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization [ZDXMHT-1-13]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
- Flagship Major Development of Jiangsu Higher Education Institutions [PPZY2015A070]
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Inspired by that the multi-target inhibitors against receptor tyrosine kinases (RTKs) have significantly improved the effect of clinical treatment for cancer, and based on the chemical structure of Linifanib (ABT-869, Abbott), two series of diaryl-ureas with novel isoxazol[3,4-b]pyridine-3-amino-structure were designed and synthesized as multi-target inhibitors against RTKs. The preliminary biological evaluation showed that several compounds exhibited comparable potency with Linifanib. Compound S21 was identified as the most potent inhibitor against Fms-like tyrosine kinase 3 (FLT-3), kinase insert domain containing receptor (KDR) and platelet-derived growth factor receptor beta (PDGFR-beta) with its IC50 values were 4 nM, 3 nM and 8 nM respectively, it also showed potent inhibitory activities against several cancer cells.
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