TY - JOUR
T1 - Binding investigation and preliminary optimisation of the 3-amino-1,2,4-triazin-5(2H)-one core for the development of new Fyn inhibitors
AU - Poli, Giulio
AU - Lapillo, Margherita
AU - Granchi, Carlotta
AU - Caciolla, Jessica
AU - Mouawad, Nayla
AU - Caligiuri, Isabella
AU - Rizzolio, Flavio
AU - Langer, Thierry
AU - Minutolo, Filippo
AU - Tuccinardi, Tiziano
PY - 2018/1/1
Y1 - 2018/1/1
N2 - 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).
AB - 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).
KW - drug design
KW - Fyn kinase
KW - kinase inhibitors
KW - molecular modelling
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U2 - 10.1080/14756366.2018.1469017
DO - 10.1080/14756366.2018.1469017
M3 - Article
C2 - 29747534
AN - SCOPUS:85046896151
VL - 33
SP - 956
EP - 961
JO - Journal of Enzyme Inhibition and Medicinal Chemistry
JF - Journal of Enzyme Inhibition and Medicinal Chemistry
SN - 1475-6366
IS - 1
ER -