Overexpressed AXL kinase is involved in various human malignancies, which incurs tumor progression, poor prognosis, and drug resistance. Suppression of the aberrant AXL axis with genetic tools or small-molecule inhibitors has achieved valid antitumor efficacies in both preclinical studies and clinical antitumor campaigns. Herein we will report the design, synthesis, and structure-activity relationship (SAR) exploration of a series of anilinopyrimidine type II AXL inhibitors. Among these inhibitors, 4l exhibited the enzymatic AXL and cellular BaF3/TEL-AXL IC50 values of 0.5 nM and less than 0.2 nM, respectively. Western blot analysis displayed that 4l dose-dependently inhibited the phosphorylation of AXL and its downstream cascade Akt, which was better than that of the reference control R428. Moreover, 4l markedly suppressed the AXL/GAS6-mediated migration in NCI-H1299 cells.
Keywords: AXL; Anilinopyrimidines; SAR; Type II inhibitors.
© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.