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

Linsheng Zhuo; Mengqin Guo; Siyi Zhang; Junbo Wu; Mingshu Wang; Yang Shen; Xue Peng; Zhen Wang; Weifan Jiang; Wei Huang

doi:10.1016/j.ejmech.2023.116090

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. Epub 2023 Dec 30.

Authors

Linsheng Zhuo¹, Mengqin Guo², Siyi Zhang³, Junbo Wu⁴, Mingshu Wang⁵, Yang Shen⁶, Xue Peng³, Zhen Wang³, Weifan Jiang⁷, Wei Huang⁸

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.

MeSH terms

Antineoplastic Agents* / chemistry
Antineoplastic Agents* / pharmacology
Cell Line, Tumor
Cell Proliferation
Humans
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors* / chemistry
Protein Kinase Inhibitors* / pharmacology
Structure-Activity Relationship

Substances

Protein Kinase Inhibitors
Antineoplastic Agents