Abstract
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 (IC50 = 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, IC50 = 0.76 μM).
Keywords:
Fyn kinase; drug design; kinase inhibitors; molecular modelling.
MeSH terms
-
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 Screening Assays, Antitumor
-
Humans
-
Models, Molecular
-
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
-
Structure-Activity Relationship
Substances
-
Antineoplastic Agents
-
Protein Kinase Inhibitors
-
Cytosine
-
6-azacytosine
-
Proto-Oncogene Proteins c-fyn
Grants and funding
We are grateful to the University of Pisa (Progetti di Ricerca di Ateneo, PRA-2017–51) for funding.