Design and synthesis of constrained analogs of LCRF-0004 as potent RON tyrosine kinase inhibitors

Bioorg Med Chem Lett. 2015 Sep 1;25(17):3706-10. doi: 10.1016/j.bmcl.2015.06.034. Epub 2015 Jun 15.

Abstract

New fused bicyclic lactam head groups as rigidified analogs of thieno[3,2-b]pyridine-based kinase inhibitor LCRF-0004 were designed and synthesized. Depending on the functionalities and the size of these bicyclic head groups, potent inhibitors of RON tyrosine kinase with various level of selectivity against c-Met tyrosine kinase were obtained.

Keywords: Bicyclic head group; Homology model; Molecular docking; RON; RTK inhibitors; c-Met.

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor / drug effects
  • Chemistry Techniques, Synthetic
  • Drug Design
  • Drug Evaluation, Preclinical / methods
  • Heterocyclic Compounds, 2-Ring / chemistry*
  • Humans
  • Inhibitory Concentration 50
  • Lactams / chemistry
  • Molecular Docking Simulation
  • Molecular Targeted Therapy
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-met / chemistry
  • Pyrazoles / chemistry*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Stomach Neoplasms / drug therapy
  • Stomach Neoplasms / pathology

Substances

  • Antineoplastic Agents
  • Heterocyclic Compounds, 2-Ring
  • LCRF-0004
  • Lactams
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Proto-Oncogene Proteins c-met
  • RON protein
  • Receptor Protein-Tyrosine Kinases