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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antineoplastic Agents / pharmacology*
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Cell Adhesion
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Cell Proliferation / drug effects
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Cell Survival
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Dose-Response Relationship, Drug
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Drug Design*
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Drug Screening Assays, Antitumor
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Humans
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Inhibitory Concentration 50
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Models, Molecular
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Molecular Targeted Therapy
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Neuroblastoma / drug therapy
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Neuroblastoma / pathology
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-abl / metabolism
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Pyrazoles / chemical synthesis
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Pyrimidines
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Quantitative Structure-Activity Relationship
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Substrate Specificity
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src-Family Kinases / antagonists & inhibitors*
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src-Family Kinases / metabolism
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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Pyrazoles
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Pyrimidines
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Proto-Oncogene Proteins c-abl
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src-Family Kinases