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

作者：Poli Giulio; Lapillo Margherita; Granchi Carlotta; Caciolla Jessica; Mouawad Nayla; Caligiuri Isabella; Rizzolio Flavio; Langer Thierry; Minutolo Filippo; Tuccinardi Tiziano^*

来源：Journal of Enzyme Inhibition and Medicinal Chemistry, 2018, 33(1): 956-961.

DOI：10.1080/14756366.2018.1469017

• Fyn kinase
• molecular modelling
• kinase inhibitors
• drug design

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-(ben-zo[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 mu M), 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 mu M).

• 出版日期2018