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Title: Studies on the ATP Binding Site of Fyn Kinase for the Identification of New Inhibitors and Their Evaluation as Potential Agents against Tauopathies and Tumors
Authors: Tintori, Cristina
La Sala, Giuseppina
Vignaroli, Giulia
Botta, Lorenzo
Fallacara, Anna Lucia
Falchi, Federico
Zamperini, Claudio
Dreassi, Elena 
Dello Iacono, Lucia
Orioli, Donata
Biamonti, Giuseppe
Garbelli, Mirko
Lossani, Andrea
Gasparrini, Francesca
Tuccinardi, Tiziano
Laurenzana, Ilaria
Angelucci, Adriano
Maga, Giovanni
Schenone, Silvia
Brullo, Chiara
Musumeci, Francesca
Desogus, Andrea
Crespan, Emmanuele
Botta, Maurizio 
Keywords: Adenosine Triphosphate; Antineoplastic Agents; Binding Sites; Cell Proliferation; Humans; Models, Molecular; Molecular Docking Simulation; Molecular Structure; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-fyn; Pyrazoles; Pyrimidines; Signal Transduction; Structure-Activity Relationship; Tauopathies; Tumor Cells, Cultured; Molecular Medicine; Drug Discovery3003 Pharmaceutical Science; Medicine (all)
Issue Date: 2015
Project: None 
Fyn is a member of the Src-family of nonreceptor protein-tyrosine kinases. Its abnormal activity has been shown to be related to various human cancers as well as to severe pathologies,; such as Alzheimer's and Parkinson's diseases. Herein, a structure-based drug design protocol was employed aimed at identifying novel Fyn inhibitors. Two hits from commercial sources (1, 2) were found active against Fyn with K-i of about 2 mu M, while derivative 4a, derived from our internal library, showed a K-i of 0.9 mu M. A hit-to-lead optimization effort was then initiated on derivative 4a to improve its potency. Slightly modifications rapidly determine an increase in the binding affinity, with the best inhibitors 4c and 44 having K(i)s of 70 and 95 nM, respectively. Both compounds were found able to inhibit the phosphorylation of : the protein Tau in an Alzheimer's model cell line and showed antiproliferative activities against different cancer cell lines.
ISSN: 0022-2623
DOI: 10.1021/acs.jmedchem.5b00140
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