Binding investigation and preliminary optimisation of the 3-amino-1,2,4-triazin-5(2H)-one core for the development of new Fyn inhibitors
| Autor: | Margherita Lapillo, Jessica Caciolla, Tiziano Tuccinardi, Nayla Mouawad, Flavio Rizzolio, Carlotta Granchi, Giulio Poli, Thierry Langer, Isabella Caligiuri, Filippo Minutolo |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Models Molecular Cell Survival drug design Fyn kinase kinase inhibitors molecular modelling Antineoplastic Agents Binding Sites Cell Line Tumor Cell Proliferation Cytosine Dose-Response Relationship Drug Drug Screening Assays Antitumor Humans Molecular Structure Protein Kinase Inhibitors Proto-Oncogene Proteins c-fyn Structure-Activity Relationship Pharmacology Drug Discovery3003 Pharmaceutical Science Short Communication Settore BIO/11 - Biologia Molecolare Drug Screening Assays Cell Line Dose-Response Relationship 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine FYN Models Drug Discovery Tumor Chemistry lcsh:RM1-950 Molecular Antitumor General Medicine Hit to lead 030104 developmental biology lcsh:Therapeutics. Pharmacology Biochemistry 030220 oncology & carcinogenesis Drug Signalling pathways Tyrosine kinase Derivative (chemistry) |
| Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 33, Iss 1, Pp 956-961 (2018) Journal of Enzyme Inhibition and Medicinal Chemistry |
| ISSN: | 1475-6374 1475-6366 |
| Popis: | 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). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |