The receptor tyrosine kinase AXL has emerged as an attractive target in anticancer drug discovery. Herein, we described the discovery of a new series of 1,6-naphthyridin-4-one derivatives as potent AXL inhibitors. Starting from a low in vivo potency compound 9 which was previously reported by our group, we utilized structure-based drug design and scaffold hopping strategies to discover potent AXL inhibitors. The privileged compound 13c was a highly potent and orally bioavailable AXL inhibitor with an IC₅₀ value of 3.2 ± 0.3 nM. Compound 13c exhibited significantly improved in vivo antitumor efficacy in AXL-driven tumor xenograft mice, causing tumor regression at well-tolerated dose, and demonstrated favorable pharmacokinetic properties (MRT = 16.5 h, AUC_0-∞ = 59,815 ng h/mL) in Sprague-Dawley rats. These results suggest that 13c is a promising therapeutic candidate for AXL-targeting cancer treatment.

受体酪氨酸激酶AXL 已成为抗癌药物发现中有吸引力的靶标。在此，我们描述了一系列新的 1,6-naphthyridin-4-one 衍生物作为有效 AXL 抑制剂的发现。从我们小组先前报道的低体内效力化合物9开始，我们利用基于结构的药物设计和支架跳跃策略来发现有效的 AXL 抑制剂。专有化合物13c是一种高效且可口服生物利用的 AXL 抑制剂，IC ₅₀值为 3.2 ± 0.3 nM。化合物13c在 AXL 驱动的肿瘤异种移植小鼠中表现出显着改善的体内抗肿瘤功效，在耐受良好的剂量下引起肿瘤消退，并在 Sprague 中表现出良好的药代动力学特性（MRT = 16.5 h，AUC _0-∞ = 59,815 ng h/mL） -道利鼠。这些结果表明13c是 AXL 靶向癌症治疗的有前途的候选药物。