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

Cristina Tintori, Giuseppina La Sala, Giulia Vignaroli, Lorenzo Botta, Anna Lucia Fallacara, Federico Falchi, Marco Radi, Claudio Zamperini, Elena Dreassi, Lucia Dello Iacono, Donata Orioli, Giuseppe Biamonti, Mirko Garbelli, Andrea Lossani, Francesca Gasparrini, Tiziano Tuccinardi, Ilaria Laurenzana, Adriano Angelucci, Giovanni Maga, Silvia SchenoneChiara Brullo, Francesca Musumeci, Andrea Desogus, Emmanuele Crespan, Maurizio Botta

Research output: Contribution to journalArticlepeer-review

Abstract

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).

Original languageEnglish
Pages (from-to)4590-4609
Number of pages20
JournalJournal of Medicinal Chemistry
Volume58
Issue number11
DOIs
Publication statusPublished - Jun 11 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery
  • Medicine(all)

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