Discovery of highly potent, selective, covalent inhibitors of JAK3

Bioorg Med Chem Lett. 2017 Oct 15;27(20):4622-4625. doi: 10.1016/j.bmcl.2017.09.023. Epub 2017 Sep 11.

Abstract

A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.

Keywords: Covalent; Irreversible inhibitor; JAK3.

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Cell Line
  • Cell Survival / drug effects
  • Drug Evaluation, Preclinical
  • Humans
  • Inhibitory Concentration 50
  • Janus Kinase 1 / antagonists & inhibitors
  • Janus Kinase 1 / metabolism
  • Janus Kinase 2 / antagonists & inhibitors
  • Janus Kinase 2 / metabolism
  • Janus Kinase 3 / antagonists & inhibitors*
  • Janus Kinase 3 / metabolism
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • Janus Kinase 1
  • Janus Kinase 2
  • Janus Kinase 3