Journal of Medicinal Chemistry p. 4590 - 4609 (2015)
Update date:2022-08-15
Topics:
Tintori, Cristina
La Sala, Giuseppina
Vignaroli, Giulia
Botta, Lorenzo
Fallacara, Anna Lucia
Falchi, Federico
Radi, Marco
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
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 Ki of about 2 μM, while derivative 4a, derived from our internal library, showed a Ki of 0.9 μM. 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 4d having Kis 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. (Chemical Equation Presented).
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