Hit-to-lead optimization and kinase selectivity of imidazo[1,2-a]quinoxalin-4-amine derived JNK1 inhibitors

Bioorg Med Chem Lett. 2013 Sep 15;23(18):5217-22. doi: 10.1016/j.bmcl.2013.06.087. Epub 2013 Jul 8.

Abstract

As the result of a rhJNK1 HTS, the imidazo[1,2-a]quinoxaline 1 was identified as a 1.6 μM rhJNK1 inhibitor. Optimization of this compound lead to AX13587 (rhJNK1 IC50=160 nM) which was co-crystallized with JNK1 to identify key molecular interactions. Kinase profiling against 125+ kinases revealed AX13587 was an inhibitor of JNK, MAST3, and MAST4 whereas its methylene homolog AX14373 (native JNK1 IC50=47 nM) was a highly specific JNK inhibitor.

Keywords: AX13587; AX14373; Imidazo[1,2-a]quinoxalin-4-amine; JNK1 inhibitor; Kinase profiling.

MeSH terms

  • Catalytic Domain / drug effects
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Mitogen-Activated Protein Kinase 8 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Quinoxalines / chemical synthesis
  • Quinoxalines / chemistry
  • Quinoxalines / pharmacology*
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • Imidazoles
  • Protein Kinase Inhibitors
  • Quinoxalines
  • Recombinant Proteins
  • imidazo(1,2-a)quinoxalin-4-amine
  • Mitogen-Activated Protein Kinase 8