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.
Publication types
-
Evaluation Study
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adenosine Triphosphate / metabolism*
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology*
-
Binding Sites
-
Cell Proliferation / drug effects
-
Humans
-
Models, Molecular
-
Molecular Docking Simulation
-
Molecular Structure
-
Neoplasms / drug therapy*
-
Neoplasms / enzymology
-
Phosphorylation / drug effects
-
Protein Kinase Inhibitors / chemistry
-
Protein Kinase Inhibitors / pharmacology*
-
Proto-Oncogene Proteins c-fyn / antagonists & inhibitors*
-
Proto-Oncogene Proteins c-fyn / metabolism
-
Pyrazoles / chemistry
-
Pyrazoles / pharmacology*
-
Pyrimidines / chemistry
-
Pyrimidines / pharmacology*
-
Signal Transduction / drug effects
-
Structure-Activity Relationship
-
Tauopathies / drug therapy*
-
Tauopathies / enzymology
-
Tumor Cells, Cultured
Substances
-
1-(2-chloro-2-phenylethyl)-3-(4-methylphenyl)-1H-pyrazolo(3,4-d)pyrimidin-4-amine
-
3-(4-chlorophenyl)-1-(2-chloro-2-phenylethyl)-1H-pyrazolo(3,4-d)pyrimidin-4-amine
-
Antineoplastic Agents
-
Protein Kinase Inhibitors
-
Pyrazoles
-
Pyrimidines
-
Adenosine Triphosphate
-
Proto-Oncogene Proteins c-fyn