Identification of potent c-Src inhibitors strongly affecting the proliferation of human neuroblastoma cells

Bioorg Med Chem Lett. 2011 Oct 1;21(19):5928-33. doi: 10.1016/j.bmcl.2011.07.079. Epub 2011 Jul 29.

Abstract

Neuroblastoma (NB) represents the most common extracranial paediatric solid tumor for which no specific FDA-approved treatment is currently available. The tyrosine kinase c-Src has been reported to play an important role in the differentiation, cell-adhesion and survival of NB cells. Starting from dual Src/Abl inhibitors previously found active in NB cell lines (1-3), small modification of the original structures almost abolished the Abl activity with a contemporary improvement of affinity and specificity for c-Src. Among the synthesized compounds, the most potent c-Src inhibitor (10a) showed a very interesting antiproliferative activity in SH-SY5Y cells with an IC(50) of 80 nM and a favourable ADME profile. A 3D SAR analysis was also attempted and may guide the design of more potent c-Src inhibitors as potential agents for NB treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Cell Adhesion
  • Cell Proliferation / drug effects
  • Cell Survival
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Drug Screening Assays, Antitumor
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Targeted Therapy
  • Neuroblastoma / drug therapy
  • Neuroblastoma / pathology
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-abl / metabolism
  • Pyrazoles / chemical synthesis
  • Pyrimidines
  • Quantitative Structure-Activity Relationship
  • Substrate Specificity
  • src-Family Kinases / antagonists & inhibitors*
  • src-Family Kinases / metabolism

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Proto-Oncogene Proteins c-abl
  • src-Family Kinases