Discovery of benzodioxane analogues as lead candidates of AIMP2-DX2 inhibitors

Bioorg Med Chem Lett. 2022 Oct 1:73:128889. doi: 10.1016/j.bmcl.2022.128889. Epub 2022 Jul 13.

Abstract

Aminoacyl-tRNA synthetase (ARS) interacting multifunctional protein2 (AIMP2) plays a vital role in protein synthesis. However, a splicing variant in which the second of the four exons of AIMP2 is deleted, inhibits the tumor suppression activity of AIMP2. Herein, we describe our discovery of series of potent AIMP2-DX2 inhibitors that are targeting lung cancer. Optimization of series using ligand-based drug design strategy led to discovery of compound 35, a potent AIMP2-DX2 inhibitor that is the most efficacious in H460 and A549 cells. This benzodioxane series may represent good starting points for further lead optimization of the identification potential drug candidates for the AIMP2-DX2 targeted treatment of lung cancer.

Keywords: AIMP2-DX2; Ligand-based drug design; Lung cancer; SAR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Amino Acyl-tRNA Synthetases*
  • Cell Line, Tumor
  • Exons
  • Humans
  • Lung Neoplasms* / pathology
  • Nuclear Proteins

Substances

  • AIMP2 protein, human
  • Nuclear Proteins
  • Amino Acyl-tRNA Synthetases