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

  • Eur J Med Chem. 2024 Feb 5:265:116045. doi: 10.1016/j.ejmech.2023.116045.
Yaohan Lan  1 ,  Xia Peng  2 ,  Yinchun Ji  2 ,  Yi Su  2 ,  Wenhu Duan  3 ,  Jing Ai  4 ,  Hefeng Zhang  5
Affiliations
  • 1. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
  • 2. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China.
  • 3. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China.
  • 4. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China; Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China. Electronic address: [email protected].
  • 5. Department of Medicinal Chemistry, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai, 201203, China. Electronic address: [email protected].
PMID: 38128234 DOI: 10.1016/j.ejmech.2023.116045
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.

Keywords
1,6-Naphthyridin-4-one derivatives; AXL inhibitor; In vivo antitumor efficacy; Scaffold hopping; Structure-based drug design.
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