Discovery of 3‑Aminopyrazole Derivatives as New Potent and Orally Bioavailable AXL Inhibitors

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-β1-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.