title: Identification of potent c-Src inhibitors strongly affecting the proliferation of human neuroblastoma cells.
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.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, University of Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Radi
authors.forename: Chiara
authors.initials: C
authors.lastname: Brullo
authors.forename: Emmanuele
authors.initials: E
authors.lastname: Crespan
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.forename: Francesca
authors.initials: F
authors.lastname: Musumeci
authors.forename: Mariangela
authors.initials: M
authors.lastname: Biava
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Elena
authors.initials: E
authors.lastname: Dreassi
authors.forename: Claudio
authors.initials: C
authors.lastname: Zamperini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Dafne
authors.initials: D
authors.lastname: Pagano
authors.forename: Adriano
authors.initials: A
authors.lastname: Angelucci
authors.forename: Mauro
authors.initials: M
authors.lastname: Bologna
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002448:Cell Adhesion; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis; D011743:Pyrimidines; D021281:Quantitative Structure-Activity Relationship; D013379:Substrate Specificity; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases