Computer aided drug discovery of highly ligand efficient, low molecular weight imidazopyridine analogs as FLT3 inhibitors

Eur J Med Chem. 2015 Apr 13:94:123-31. doi: 10.1016/j.ejmech.2015.02.052. Epub 2015 Feb 28.

Abstract

The FLT3 kinase represents an attractive target to effectively treat AML. Unfortunately, no FLT3 targeted therapeutic is currently approved. In line with our continued interests in treating kinase related disease for anti-FLT3 mutant activity, we utilized pioneering synthetic methodology in combination with computer aided drug discovery and identified low molecular weight, highly ligand efficient, FLT3 kinase inhibitors. Compounds were analyzed for biochemical inhibition, their ability to selectively inhibit cell proliferation, for FLT3 mutant activity, and preliminary aqueous solubility. Validated hits were discovered that can serve as starting platforms for lead candidates.

Keywords: AML; Computer aided drug discovery; FLT3; Kinase inhibitor; Ligand efficiency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line / drug effects
  • Chemistry Techniques, Synthetic
  • Computer-Aided Design*
  • Drug Discovery / methods*
  • Drug Evaluation, Preclinical / methods
  • Libraries, Digital
  • Ligands
  • Mice
  • Molecular Weight
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / chemistry
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • fms-Like Tyrosine Kinase 3 / antagonists & inhibitors*
  • fms-Like Tyrosine Kinase 3 / chemistry

Substances

  • Ligands
  • Protein Kinase Inhibitors
  • Pyridines
  • Small Molecule Libraries
  • FLT3 protein, human
  • fms-Like Tyrosine Kinase 3