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极具吸引力的靶点。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。从先前报道过的低体内效力效力化合物9开始我们小组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。专利化合物13c是一种高效、口服生物可利用的AXL抑制剂，IC值为₅₀ 值为 3.2 ± 0.3 nM。化合物13c在AXL驱动的肿瘤中表现出显着改善的体内抗肿瘤功效异种移植小鼠，在耐受良好的剂量下引起肿瘤消退，并表现出良好的药代动力学特性（MRT = 16.5 h，AUC_0-∞ = 59,815 ng h/mL) 在 Sprague-Dawley 大鼠中。这些结果表明13c是 AXL 靶向癌症治疗的有前途的候选药物。