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

Giulio Poli, Margherita Lapillo, Carlotta Granchi, Jessica Caciolla, Nayla Mouawad, Isabella Caligiuri, Flavio Rizzolio, Thierry Langer, Filippo Minutolo, Tiziano Tuccinardi

Research output: Contribution to journalArticlepeer-review

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).

Original languageEnglish
Pages (from-to)956-961
Number of pages6
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume33
Issue number1
DOIs
Publication statusPublished - Jan 1 2018

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery

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