Structure-activity relationship study of 1,6-naphthyridinone derivatives as selective type II AXL inhibitors with potent antitumor efficacy

  • Eur J Med Chem. 2024 Feb 5:265:116090. doi: 10.1016/j.ejmech.2023.116090.
Linsheng Zhuo  1 ,  Mengqin Guo  2 ,  Siyi Zhang  3 ,  Junbo Wu  4 ,  Mingshu Wang  5 ,  Yang Shen  6 ,  Xue Peng  3 ,  Zhen Wang  3 ,  Weifan Jiang  7 ,  Wei Huang  8
Affiliations
  • 1. Postdoctoral Station for Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China; School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
  • 2. School of Pharmaceutical Sciences, Wuhan University, Wuhan, Hubei, 430071, China.
  • 3. School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 4. Department of Colorectal Surgery, Hengyang Central Hospital, Hengyang, Hunan, 421001, China.
  • 5. Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan, 430079, China.
  • 6. Postdoctoral Station for Basic Medicine, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 7. School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China. Electronic address: [email protected].
  • 8. Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, International Joint Research Center for Intelligent Biosensor Technology and Health, College of Chemistry, Central China Normal University, Wuhan, 430079, China. Electronic address: [email protected].
PMID: 38169272 DOI: 10.1016/j.ejmech.2023.116090
Abstract

The role of Axl in various oncogenic processes has made it an attractive target for Cancer therapy. Currently, kinase selectivity profiles, especially circumventing MET inhibition, remain a scientific issue of great interest in the discovery of selective type II Axl inhibitors. Starting from a dual MET/AXL-targeted lead structure from our previous work, we optimized a 1,6-naphthyridinone series using molecular modeling-assisted compound design to improve Axl potency and selectivity over MET, resulting in the potent and selective type II AXL-targeted compound 25c. This showed excellent Axl inhibitory activity (IC50 = 1.1 nM) and 343-fold selectivity over the highly homologous kinase MET in biochemical assays. Moreover, compound 25c significantly inhibited AXL-driven cell proliferation, dose-dependently suppressed 4T1 cell migration and invasion, and induced Apoptosis. Compound 25c also showed noticeable antitumor efficacy in a BaF3/TEL-AXL xenograft model at well-tolerated doses. Overall, this study presented a potent and selective type II AXL-targeted lead compound for further drug discovery.

Keywords
1,6-Naphthyridone; AXL kinase inhibitor; Kinase selectivity; Quinazoline.
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