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Discovery of a 1,6-naphthyridin-4-one-based AXL inhibitor with improved pharmacokinetics and enhanced in vivo antitumor efficacy

文献类型：期刊论文

作者Lan, Yaohan1,3; Peng, Xia4; Ji, Yinchun4; Su, Yi4; Duan, Wenhu1,2,3; Ai, Jing3,4; Zhang, Hefeng1
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2024-02-05
卷号265页码:17
关键词AXL inhibitor In vivo antitumor efficacy 6-Naphthyridin-4-one derivatives Scaffold hopping Structure-based drug design
ISSN号0223-5234
DOI10.1016/j.ejmech.2023.116045
通讯作者Ai, Jing(jai@simm.ac.cn) ; Zhang, Hefeng(zhanghefeng1@simm.ac.cn)
英文摘要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 infinity = 59,815 ng h/mL) in Sprague-Dawley rats. These results suggest that 13c is a promising therapeutic candidate for AXL-targeting cancer treatment.
WOS关键词KINASE ; CANCER ; ACTIVATION ; DESIGN
资助项目China Postdoctoral Science Foundation[2023T160663] ; Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning[SYS202205] ; Shandong Laboratory Program[81821005] ; Natural Science Foundation of China for Innovation Research Group ; [2020CXJQ02]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:001147236800001
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/308969]  
专题新药研究国家重点实验室
通讯作者Ai, Jing; Zhang, Hefeng
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, Dept Med Chem, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
2.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China
3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med SIMM, State Key Lab Drug Res, Div Antitumor Pharmacol, 555 Zu Chong Zhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Lan, Yaohan,Peng, Xia,Ji, Yinchun,et al. Discovery of a 1,6-naphthyridin-4-one-based AXL inhibitor with improved pharmacokinetics and enhanced in vivo antitumor efficacy[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2024,265:17.
APA Lan, Yaohan.,Peng, Xia.,Ji, Yinchun.,Su, Yi.,Duan, Wenhu.,...&Zhang, Hefeng.(2024).Discovery of a 1,6-naphthyridin-4-one-based AXL inhibitor with improved pharmacokinetics and enhanced in vivo antitumor efficacy.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,265,17.
MLA Lan, Yaohan,et al."Discovery of a 1,6-naphthyridin-4-one-based AXL inhibitor with improved pharmacokinetics and enhanced in vivo antitumor efficacy".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 265(2024):17.

入库方式： OAI收割

来源：上海药物研究所

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