Structure-based design and synthesis of bicyclic fused-pyridines as MEK inhibitors

Bioorg Med Chem Lett. 2014 Jun 1;24(11):2555-9. doi: 10.1016/j.bmcl.2014.03.086. Epub 2014 Apr 3.

Abstract

The MAPK pathway is identified as one of the most important pathways involved in cell proliferation and differentiation. A key kinase in the pathway, the Mitogen-activated protein kinase kinase (MEK) is recognized as a promising target for antitumor drugs. Structure-based design and optimization of known MEK inhibitors resulted in identification of compound 10a as a potent non-ATP competitive MEK inhibitor in both in vitro and in vivo tests.

Keywords: Bicyclic; Cancer; Fused-pyridine; MEK; SBDD.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Bridged Bicyclo Compounds / chemical synthesis
  • Bridged Bicyclo Compounds / chemistry
  • Bridged Bicyclo Compounds / pharmacology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Design*
  • HCT116 Cells
  • Humans
  • Mice
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / enzymology
  • Microsomes, Liver / metabolism
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Models, Molecular
  • Molecular Structure
  • Neoplasms, Experimental / drug therapy*
  • Neoplasms, Experimental / pathology
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Bridged Bicyclo Compounds
  • Protein Kinase Inhibitors
  • Pyridines
  • Mitogen-Activated Protein Kinase Kinases