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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.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2015 Jun 11; Vol. 58 (11), pp. 4590-609. Date of Electronic Publication: 2015 May 20. - Publication Year :
- 2015
-
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 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.
- Subjects :
- Antineoplastic Agents chemistry
Binding Sites
Cell Proliferation drug effects
Humans
Models, Molecular
Molecular Docking Simulation
Molecular Structure
Neoplasms enzymology
Phosphorylation drug effects
Protein Kinase Inhibitors chemistry
Proto-Oncogene Proteins c-fyn metabolism
Pyrazoles chemistry
Pyrimidines chemistry
Signal Transduction drug effects
Structure-Activity Relationship
Tauopathies enzymology
Tumor Cells, Cultured
Adenosine Triphosphate metabolism
Antineoplastic Agents pharmacology
Neoplasms drug therapy
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins c-fyn antagonists & inhibitors
Pyrazoles pharmacology
Pyrimidines pharmacology
Tauopathies drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 58
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 25923950
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.5b00140