期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 22, 页码 15374-15390出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01346
关键词
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资金
- Ministry of Science and Technology of the People's Republic of China [SQ2019YFE010401]
- National Natural Science Foundation of China [81874284, 818201029, 8182010804, 22037003, 81973158]
- Natural Science Foundation of China for Innovation Research Group [81821005]
- Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning [2020CXJQ02]
- State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry
The study describes the discovery of 3-aminopyrazole derivatives as potent and selective AXL kinase inhibitors. One representative compound, 6li, showed strong inhibitory activity against AXL enzymatic activity and demonstrated significant antitumor efficacy in vitro and in vivo.
The receptor tyrosine kinase AXL is a promising target for anticancer drug discovery. Herein, we describe the discovery of 3-aminopyrazole derivatives as new potent and selective AXL kinase inhibitors. One of the representative compounds, 6li, potently inhibited AXL enzymatic activity with an IC50 value of 1.6 nM, and tightly bound with AXL protein with a Kd value of 0.26 nM, while was obviously less potent against most of the 403 wild-type kinases evaluated. Cell-based assays demonstrated that compound 6li potently inhibited AXL signaling, suppressed Ba/F3-TEL-AXL cell proliferation, reversed TGF-beta 1-induced epithelial-mesenchymal transition, and dose-dependently impeded cancer cell migration and invasion. Compound 6li also showed reasonable pharmacokinetic properties in rats and exhibited significant in vivo antitumor efficacy in a xenograft model of highly metastatic murine breast cancer 4T1 cells. Taken together, this study provides a new potent and selective AXL inhibitor for further anticancer drug discovery.
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