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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• 作者：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 Schenone ; Chiara Brullo ; Francesca Musumeci ; Andrea Desogus ; Emmanuele Crespan ; Maurizio Botta
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：June 11, 2015
• 年：2015
• 卷：58
• 期：11
• 页码：4590-4609
• 全文大小：849K
• ISSN：1520-4804

文摘

Fyn is a member of the Src-family of nonreceptor protein鈥搕yrosine kinases. Its abnormal activity has been shown to be related to various human cancers as well as to severe pathologies, such as Alzheimer鈥檚 and Parkinson鈥檚 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 渭M, while derivative 4a, derived from our internal library, showed a K_i of 0.9 渭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 4d having K_is of 70 and 95 nM, respectively. Both compounds were found able to inhibit the phosphorylation of the protein Tau in an Alzheimer鈥檚 model cell line and showed antiproliferative activities against different cancer cell lines.