Structure-Based Drug Discovery of Triazine Derivatives as Potent and Orally Bioavailable AXL Inhibitors for Cancer Therapy

The receptor tyrosine kinase AXL is overexpressed in various cancers. There is considerable interest in developing AXL inhibitors to overcome tumor resistance to immunotherapy and chemotherapy. Herein, we report a novel AXL inhibitor 4j, which was discovered through structure-based drug design, SAR-driven optimization, and pharmacokinetic parameters screening. The candidate compound demonstrated excellent enzymatic activity, potent antiproliferative activity and selectivity, favorable oral bioavailability, and acceptable pharmacokinetic properties. When paired with an anti-PD-1 antibody, 4j exhibited promising therapeutic efficacy and significant synergistic effects in vivo. Taken together, 4j is an innovative therapeutic candidate for the treatment of malignant tumors.