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.
- 1. Dipartimento Farmaco Chimico Tecnologico, University of Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy.
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.