Synthesis and profiling of a 3-aminopyridin-2-one-based kinase targeted fragment library: Identification of 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one scaffold for monopolar spindle 1 (MPS1) and Aurora kinases inhibition

Bioorg Med Chem. 2018 Jul 15;26(11):3021-3029. doi: 10.1016/j.bmc.2018.04.033. Epub 2018 Apr 17.

Abstract

Screening a 3-aminopyridin-2-one based fragment library against a 26-kinase panel representative of the human kinome identified 3-amino-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2(1H)-one (2) and 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one (3) as ligand efficient inhibitors of the mitotic kinase Monopolar Spindle 1 (MPS1) and the Aurora kinase family. These kinases are well recognised as attractive targets for therapeutic intervention for treating cancer. Elucidation of the binding mode of these fragments and their analogues has been carried out by X-ray crystallography. Structural studies have identified key interactions with a conserved lysine residue and have highlighted potential regions of MPS1 which could be targeted to improve activity and selectivity.

Keywords: 3-Aminopyridin-2-one; Aurora kinase; Fragment compound library; MPS1 kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / chemical synthesis
  • Aminopyridines / chemistry*
  • Aminopyridines / pharmacology
  • Crystallography, X-Ray
  • Drug Delivery Systems*
  • Inhibitory Concentration 50
  • Molecular Structure
  • Peptide Fragments / chemical synthesis*
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology
  • Peptide Library
  • Protein Kinase Inhibitors* / chemical synthesis
  • Protein Kinase Inhibitors* / chemistry
  • Protein Kinase Inhibitors* / pharmacology

Substances

  • Aminopyridines
  • Peptide Fragments
  • Peptide Library
  • Protein Kinase Inhibitors