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    • Discovery of a 1,6-Naphthyridin-4-one-based AXL Inhibitor with Improved Pharmacokinetics and Enhanced in Vivo Antitumor Efficacy

    Yaohan Lan,Xia Peng,Yinchun Ji,Yi Su,Wenhu Duan,Jing Ai,Hefeng Zhang

    European Journal of Medicinal Chemistry（2023）

    Chinese Acad Sci | Univ Chinese Acad Sci

    Cited 1|Views27
    Abstract
    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, AUC0-∞ = 59,815 ng h/mL) in Sprague-Dawley rats. These results suggest that 13c is a promising therapeutic candidate for AXL-targeting cancer treatment.
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    AXL inhibitor,In vivo antitumor efficacy,6-Naphthyridin-4-one derivatives,Scaffold hopping,Structure-based drug design
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    Related Papers

    Recent Discovery and Development of AXL Inhibitors As Antitumor Agents

    Zihang Liu,Li Chen,Jifa Zhang,Jun Yang,Xue Xiao,Lianhai Shan,Wuyu Mao
    European Journal of Medicinal Chemistry 2024

    被引用0

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    【要点】：该论文描述了通过结构基于药物设计和骨架跳跃策略发现的一种新型1,6-萘啶-4-酮衍生物系列作为AXL抑制剂，其中优选化合物13c具有高potency和口服生物利用度，并且在AXL驱动的肿瘤异种移植小鼠中显示出显著增强的体内抗肿瘤疗效。
    

    【方法】：采用结构-基于药物设计和骨架跳跃策略。
    

    【实验】：实验在SD大鼠中进行，使用优选化合物13c，结果显示其具有良好的药代动力学特性，并对AXL驱动的肿瘤异种移植小鼠模型具有显著的体内抗肿瘤疗效。IC50值为3.2 ± 0.3 nM，中位存活时间（MRT）为16.5小时，area under the curve (AUC0 infinity)为59,815 ng h/mL。