Discovery of a Selective and Potent Inhibitor of Mitogen-Activated Protein Kinase-Interacting Kinases 1 and 2 (MNK1/2) Utilizing Structure-Based Drug Design

J Med Chem. 2016 Apr 14;59(7):3034-45. doi: 10.1021/acs.jmedchem.5b01657. Epub 2016 Mar 29.

Abstract

The discovery of a highly potent and selective small molecule inhibitor 9 for in vitro target validation of MNK1/2 kinases is described. The aminopyrazine benzimidazole series was derived from an HTS hit and optimized by utilization of a docking model, conformation analysis, and binding pocket comparison against antitargets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Caco-2 Cells / drug effects
  • Drug Design
  • High-Throughput Screening Assays / methods
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Molecular Docking Simulation
  • Permeability
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / metabolism
  • Solubility
  • Structure-Activity Relationship

Substances

  • Intracellular Signaling Peptides and Proteins
  • Protein Kinase Inhibitors
  • MKNK1 protein, human
  • MKNK2 protein, human
  • Protein Serine-Threonine Kinases