Binding investigation and preliminary optimisation of the 3-amino-1, 2, 4-triazin-5(2H)-one core for the development of new Fyn inhibitors. (1st January 2018)

• Record Type: Journal Article
• Authors: Poli, Giulio; Lapillo, Margherita; Granchi, Carlotta; Caciolla, Jessica; Mouawad, Nayla; Caligiuri, Isabella; Rizzolio, Flavio; Langer, Thierry; Minutolo, Filippo; Tuccinardi, Tiziano
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 33:Number 1(2018)
• Page Start: 956
• Page End: 961
• Publication Date: 2018-01-01
• Subjects: Fyn kinase -- molecular modelling -- kinase inhibitors -- drug design; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2018.1469017
• Languages: English
• ISSNs: 1475-6366

Abstract

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(2 H )-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(2 H )-one scaffold and started a preliminary hit to lead optimisation. This analysis led us to confirm the hypothesised binding mode ofVS6 and to identify a new derivative that is about 6-fold more active thanVS6 (compound3, IC50 = 0.76 μM).