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J Med Chem. 2015 Jun 11;58(11):4590-609. doi: 10.1021/acs.jmedchem.5b00140. Epub 2015 May 20.

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.

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†Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. De Gasperi 2, I-53100 Siena, Italy.
‡Dipartimento di Chimica e Tecnologie del Farmaco, Università La Sapienza, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
§Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, I-27100 Pavia, Italy.
∥Dipartimento di Medicina Molecolare, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy.
⊥Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
#Laboratory of Preclinical and Translational Research, IRCCS-Centro di Riferimento Oncologico Basilicata (CROB), Via Padre Pio 1, Rionero in Vulture 85028 Potenza Italy.
∇Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila, Via Vetoio, 67100 Coppito, L'Aquila, Italy.
○Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, I-16132 Genova, Italy.
◆Biotechnology College of Science and Technology, Temple University, Biolife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, Pennsylvania 19122, United States.


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 μM, while derivative 4a, derived from our internal library, showed a K(i) 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 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.

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