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 mu M, while derivative 4a, derived from our internal library, showed a K-i of 0.9 mu 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 44 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.

Tintori, C., La Sala, G., Vignaroli, G., Botta, L., Fallacara, A.L., Falchi, F., et al. (2015). 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. JOURNAL OF MEDICINAL CHEMISTRY, 58(11), 4590-4609 [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

RADI, MARCO;DREASSI, ELENA;BOTTA, MAURIZIO
2015-01-01

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 K-i of about 2 mu M, while derivative 4a, derived from our internal library, showed a K-i of 0.9 mu 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 44 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.
Tintori, C., La Sala, G., Vignaroli, G., Botta, L., Fallacara, A.L., Falchi, F., et al. (2015). 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. JOURNAL OF MEDICINAL CHEMISTRY, 58(11), 4590-4609 [10.1021/acs.jmedchem.5b00140].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/982066
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