Synthesis and anti-tumor activity of EF24 analogues as IKKβ inhibitors

Eur J Med Chem. 2018 Jan 20:144:218-228. doi: 10.1016/j.ejmech.2017.11.077. Epub 2017 Dec 7.

Abstract

EF24 is an IKKβ inhibitor (IC50: 72 μM) containing various anti-tumor activities. In this study, a series of EF24 analogs targeting IKKβ were designed and synthesized. Several IKKβ inhibitors with better activities than EF24 were screened out and B3 showed best IKKβ inhibitory (IC50: 6.6 μM). Molecular docking and dynamic simulation experiments further confirmed this inhibitory effect. B3 obviously suppressed the viability of Hela229, A549, SGC-7901 and MGC-803 cells. Then, in SGC-7901 and MGC-803 cells, B3 blocked the NF-κB signal pathway by inhibiting IKKβ phosphorylation, and followed arrested the cell cycle at G2/M phase by suppressing the Cyclin B1 and Cdc2 p34 expression, induced the cell apoptosis by down-regulating Bcl-2 protein and up-regulating cleaved-caspase3. Moreover, B3 significantly reduced tumor growth and suppressed the IKKβ-NF-κB signal pathway in SGC-7901 xenograft model. In total, this study present a potential IKKβ inhibitor as anti-tumor precursor.

Keywords: Anti-tumor activity; IKKβ inhibitor; Molecular docking; Synthesis.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Apoptosis / drug effects
  • Benzylidene Compounds / chemical synthesis
  • Benzylidene Compounds / chemistry*
  • Benzylidene Compounds / pharmacology*
  • Benzylidene Compounds / therapeutic use
  • Cell Line, Tumor
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • I-kappa B Kinase / antagonists & inhibitors*
  • I-kappa B Kinase / metabolism
  • Mice, Nude
  • Molecular Docking Simulation
  • NF-kappa B / metabolism
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Phosphorylation / drug effects
  • Piperidones / chemical synthesis
  • Piperidones / chemistry*
  • Piperidones / pharmacology*
  • Piperidones / therapeutic use
  • Signal Transduction / drug effects

Substances

  • 3,5-bis(2-fluorobenzylidene)piperidin-4-one
  • Antineoplastic Agents
  • Benzylidene Compounds
  • NF-kappa B
  • Piperidones
  • I-kappa B Kinase