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

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

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: lszhuo@usc.edu.cn.
  • 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: jiangwf@usc.edu.cn.
  • 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: weihuangwuhan@126.com.
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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