Binding investigation and preliminary optimisation of the 3-amino-1,2,4-triazin-5(2H)-one core for the development of new Fyn inhibitors

Fyn tyrosine kinase inhibitors are considered potential therapeutic agents for a variety of human cancers. Furthermore, the involvement of Fyn kinase in signalling pathways that lead to severe pathologies, such as Alzheimer's and Parkinson's diseases, has also been demonstrated. In this st...

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Published in:Journal of enzyme inhibition and medicinal chemistry 2018-01, Vol.33 (1), p.956-961
Main Authors: Poli, Giulio, Lapillo, Margherita, Granchi, Carlotta, Caciolla, Jessica, Mouawad, Nayla, Caligiuri, Isabella, Rizzolio, Flavio, Langer, Thierry, Minutolo, Filippo, Tuccinardi, Tiziano
Format: Article
Language:English
Subjects:
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Binding Sites - drug effects
Cell Line, Tumor
Cell Proliferation - drug effects
Cell Survival - drug effects
Cytosine - analogs & derivatives
Cytosine - chemical synthesis
Cytosine - chemistry
Cytosine - pharmacology
Dose-Response Relationship, Drug
drug design
Drug Screening Assays, Antitumor
Fyn kinase
Humans
kinase inhibitors
Models, Molecular
molecular modelling
Molecular Structure
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-fyn - antagonists & inhibitors
Proto-Oncogene Proteins c-fyn - metabolism
Short Communication
Structure-Activity Relationship
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Summary:Fyn tyrosine kinase inhibitors are considered potential therapeutic agents for a variety of human cancers. Furthermore, the involvement of Fyn kinase in signalling pathways that lead to severe pathologies, such as Alzheimer's and Parkinson's diseases, has also been demonstrated. In this study, starting from 3-(benzo[d][1,3]dioxol-5-ylamino)-6-methyl-1,2,4-triazin-5(2H)-one (VS6), a hit compound that showed a micromolar inhibition of Fyn (IC 50  = 4.8 μM), we computationally investigated the binding interactions of the 3-amino-1,2,4-triazin-5(2H)-one scaffold and started a preliminary hit to lead optimisation. This analysis led us to confirm the hypothesised binding mode of VS6 and to identify a new derivative that is about 6-fold more active than VS6 (compound 3, IC 50  = 0.76 μM).
ISSN:1475-6366
1475-6374
DOI:10.1080/14756366.2018.1469017