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

doi:10.1080/14756366.2018.1469017

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

Centro di Riferimento Oncologico

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	956-961
Number of pages	6
Journal	Journal of Enzyme Inhibition and Medicinal Chemistry
Volume	33
Issue number	1
DOIs	https://doi.org/10.1080/14756366.2018.1469017
Publication status	Published - Jan 1 2018

Keywords

drug design
Fyn kinase
kinase inhibitors
molecular modelling

ASJC Scopus subject areas

Pharmacology
Drug Discovery

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10.1080/14756366.2018.1469017

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Poli, G., Lapillo, M., Granchi, C., Caciolla, J., Mouawad, N., Caligiuri, I., Rizzolio, F., Langer, T., Minutolo, F., & Tuccinardi, T. (2018). Binding investigation and preliminary optimisation of the 3-amino-1,2,4-triazin-5(2H)-one core for the development of new Fyn inhibitors. Journal of Enzyme Inhibition and Medicinal Chemistry, 33(1), 956-961. https://doi.org/10.1080/14756366.2018.1469017

Binding investigation and preliminary optimisation of the 3-amino-1,2,4-triazin-5(2H)-one core for the development of new Fyn inhibitors. / Poli, Giulio; Lapillo, Margherita; Granchi, Carlotta; Caciolla, Jessica; Mouawad, Nayla; Caligiuri, Isabella ; Rizzolio, Flavio; Langer, Thierry; Minutolo, Filippo; Tuccinardi, Tiziano.

In: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 33, No. 1, 01.01.2018, p. 956-961.

Research output: Contribution to journal › Article › peer-review

Poli, G, Lapillo, M, Granchi, C, Caciolla, J, Mouawad, N, Caligiuri, I , Rizzolio, F, Langer, T, Minutolo, F & Tuccinardi, T 2018, 'Binding investigation and preliminary optimisation of the 3-amino-1,2,4-triazin-5(2H)-one core for the development of new Fyn inhibitors', Journal of Enzyme Inhibition and Medicinal Chemistry, vol. 33, no. 1, pp. 956-961. https://doi.org/10.1080/14756366.2018.1469017

Poli, Giulio ; Lapillo, Margherita ; Granchi, Carlotta ; Caciolla, Jessica ; Mouawad, Nayla ; Caligiuri, Isabella ; Rizzolio, Flavio ; Langer, Thierry ; Minutolo, Filippo ; Tuccinardi, Tiziano. / Binding investigation and preliminary optimisation of the 3-amino-1,2,4-triazin-5(2H)-one core for the development of new Fyn inhibitors. In: Journal of Enzyme Inhibition and Medicinal Chemistry. 2018 ; Vol. 33, No. 1. pp. 956-961.

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AU - Caciolla, Jessica

AU - Mouawad, Nayla

AU - Caligiuri, Isabella

AU - Rizzolio, Flavio

AU - Langer, Thierry

AU - Minutolo, Filippo

AU - Tuccinardi, Tiziano

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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).

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

Abstract

Keywords

ASJC Scopus subject areas

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