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.
Identification of Potent c-Src Inhibitors Strongly Affecting the Proliferation of Human Neuroblastoma Cells / Marco Radi; Chiara Brullo; Emmanuele Crespan; Cristina Tintori; Francesca Musumeci; Mariangela Biava; Silvia Schenone; Elena Dreassi; Claudio Zamperini; Giovanni Maga; Dafne Pagano; Adriano Angelucci; Mauro Bologna; Maurizio Botta. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - 21(2011), pp. 5928-5933. [10.1016/j.bmcl.2011.07.079]