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Discovery of a New Bioactive Molecule for Neuroblastoma
Author(s) -
Leitão Andrei,
Schramm Alexander,
Eggert Angelika
Publication year - 2013
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12148
Subject(s) - chemistry , neuroblastoma , drug discovery , small molecule , computational biology , molecule , combinatorial chemistry , biology , biochemistry , organic chemistry , genetics , cell culture
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 ( T rk) 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 T rk receptor activity. One compound ( C 390‐0031) 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 T rk kinase domain composing its structure, this molecule does not inhibit T rk A like lestaurtinib, constituting a new chemical with a yet unknown mechanism of action.