Exploration of 1-(3-chloro-4-(4-oxo-4H-chromen-2-yl)phenyl)-3-phenylurea derivatives as selective dual inhibitors of Raf1 and JNK1 kinases for anti-tumor treatment

Bioorg Med Chem. 2013 Feb 1;21(3):824-31. doi: 10.1016/j.bmc.2012.04.006. Epub 2012 Apr 11.


Based on the roles of Raf1 and JNK1 in hepatocarcinoma development, scaffold-based drug design was employed to produce a series of compounds, which subsequently were synthesized and explored as potential dual inhibitors Raf1 and JNK1 kinases for anti-tumor treatment. The compound 1-(3-chloro-4-(6-ethyl-4-oxo-4H-chromen-2-yl)phenyl)-3-(4-chloro-phenyl)urea (3d) showed 66%, 67% and 13% inhibition rate at 50 μM against Raf1, JNK1 and p38-alpha, respectively, but no effect on ERK1 and ERK2, and inhibited the expression of pERK1/2 markedly and HepG2 cells proliferation with IC(50) at 8.3 μM. Furthermore, 3d showed lower toxicity against normal liver cell-lines QSG7701 and HL7702. Molecular docking study further showed that 3d can fit into binding domain of JNK1 and Raf1. Our data suggested the activities of 3d were associated with dual inhibition of JNK1 and Raf1 kinases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Benzopyrans / chemical synthesis
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Hep G2 Cells
  • Humans
  • Mitogen-Activated Protein Kinase 8 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Models, Molecular
  • Molecular Structure
  • Phenylurea Compounds / chemical synthesis
  • Phenylurea Compounds / chemistry
  • Phenylurea Compounds / pharmacology*
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-raf / metabolism
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Benzopyrans
  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-raf
  • Mitogen-Activated Protein Kinase 8