Discovery of a new bioactive molecule for neuroblastoma

Neuroblastoma, a common pediatric malignancy of neural crest origin, is unique in its wide spectrum of clinical and biological behavior, ranging from spontaneous regression or differentiation to rapid progression and metastasis. Overexpression of neurotrophin receptors of the tyrosine kinase (Trk) family has been identified as a major prognostic and biological factor for this disease. Novel molecules were selected using cheminformatics tools (structure-based virtual screening and ligand-based virtual screening) and screened in cell-based assays to modulate Trk receptor activity. One compound (C390-0031) had a potent antiproliferative activity in dose-response studies using neuroblastoma cell lines. The molecular effects of this molecule were further characterized by using cell cycle and Western blot analysis. Interestingly, despite the presence of the anchoring fragment to the Trk kinase domain composing its structure, this molecule does not inhibit TrkA like lestaurtinib, constituting a new chemical with a yet unknown mechanism of action.