CNR ExploRA

Articolo in rivista, 2015, ENG, 10.1021/acs.jmedchem.5b00140

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

Tintori C, La Sala G, Vignaroli G, Botta L, Fallacara AL, Falchi F, Radi M, Zamperini C, Dreassi E, Dello Iacono L, Orioli D, Biamonti G, Garbelli M, Lossani A, Gasparrini F, Tuccinardi T, Laurenzana I, Angelucci A, Maga G, Schenone S, Brullo C, Musumeci F, Desogus A, Crespan E, Botta M.

Dipartimento Biotecnologie, Chimica e Farmacia, Università Degli Studi di Siena, Via A. De Gasperi 2, Siena, I-53100, Italy; Dipartimento di Chimica e Tecnologie Del Farmaco, Università la Sapienza, Piazzale Aldo Moro 5, Roma, I-00185, Italy; Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, Pavia, I-27100, Italy; Dipartimento di Medicina Molecolare, Sapienza Università di Roma, Piazzale Aldo Moro 5, Roma, 00185, Italy; Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, Pisa, 56126, Italy; Laboratory of Preclinical and Translational Research, IRCCS-Centro di Riferimento Oncologico Basilicata (CROB), Via Padre Pio 1, Rionero in Vulture, Potenza, 85028, Italy; Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila, Via Vetoio, Coppito, L'Aquila, 67100, Italy; Dipartimento di Farmacia, Università di Genova, Viale Benedetto XV 3, Genova, I-16132, Italy; Biotechnology College of Science and Technology, Temple University, Biolife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, PA, 19122, United States; Dipartimento di Farmacia, University of Parma, Parco Area delle Scienze 27/A, Parma, 43124, Italy; Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, Bologna, 40126, Italy; Department of Drug Discovery and Development, Italian Institute of Technology, Via Morego 30, Genova, 16163, Italy

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 microM, while derivative 4a, derived from our internal library, showed a K(i) of 0.9 microM. 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 activitiesagainst different cancer cell lines.

Journal of medicinal chemistry 58 (11), pp. 4590–4609