Identification and characterization of potent, selective and metabolically stable IKKβ inhibitor

Bioorg Med Chem Lett. 2016 Feb 15;26(4):1120-3. doi: 10.1016/j.bmcl.2016.01.065. Epub 2016 Jan 22.


We have previously reported the identification of a rhodanine compound (1) with well-balanced inhibitory activity against IKKβ and collagen-induced TNFα activated cells. However, we need more optimized compounds because of its instability over plasma and microsome. As part of a program directed toward the optimization of IKKβ inhibitor, we modified a substituent of parent compound to a series of functional groups. Among substituted compounds, fluorine substituent (12) on the para position of phenyl ring restored the stability toward plasma and microsome while retaining inhibitory potency and selectivity against IKKβ over other kinases. Also, we have demonstrated that compound 12 is an ATP non-competitive inhibitor and safe enough to apply to animal experiment from an acute toxicity test.

Keywords: Allosteric inhibitor; IKKβ inhibitor; NF-κB; Reumatoid arthritis.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Body Weight / drug effects
  • Female
  • Half-Life
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / metabolism
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Mice, Inbred ICR
  • Microsomes, Liver / metabolism
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Rats
  • Rhodanine / chemistry
  • Rhodanine / pharmacokinetics
  • Rhodanine / pharmacology


  • Protein Kinase Inhibitors
  • Rhodanine
  • I-kappa B Kinase