and Laboratory of Preclinical and Translational Research

Padre, Italy

and Laboratory of Preclinical and Translational Research

Padre, Italy

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PubMed | University of Genoa, CNR Institute of Molecular Genetics, University of Rome La Sapienza, Applicate and 3 more.
Type: Evaluation Studies | Journal: Journal of medicinal chemistry | Year: 2015

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 Alzheimers and Parkinsons 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 M, while derivative 4a, derived from our internal library, showed a K(i) of 0.9 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(i)s of 70 and 95 nM, respectively. Both compounds were found able to inhibit the phosphorylation of the protein Tau in an Alzheimers model cell line and showed antiproliferative activities against different cancer cell lines.

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