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New classes of potent heparanase inhibitors from ligand-based virtual screening

Heparanase is a validated target in cancer therapy and a potential target for several inflammatory pathologies. A ligand-based virtual screening of commercial libraries was performed to expand the chemical space of small-molecule inhibitors. The screening was based on similarity with known inhibitor...

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Detalles Bibliográficos
Autores principales: Pala, Daniele, Scalvini, Laura, Elisi, Gian Marco, Lodola, Alessio, Mor, Marco, Spadoni, Gilberto, Ferrara, Fabiana F., Pavoni, Emiliano, Roscilli, Giuseppe, Milazzo, Ferdinando M., Battistuzzi, Gianfranco, Rivara, Silvia, Giannini, Giuseppe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534336/
https://www.ncbi.nlm.nih.gov/pubmed/32907434
http://dx.doi.org/10.1080/14756366.2020.1811701
Descripción
Sumario:Heparanase is a validated target in cancer therapy and a potential target for several inflammatory pathologies. A ligand-based virtual screening of commercial libraries was performed to expand the chemical space of small-molecule inhibitors. The screening was based on similarity with known inhibitors and was performed in several runs, starting from literature compounds and progressing through newly discovered inhibitors. Among the fifty-five tested compounds, nineteen had IC(50) values lower than 5 µM and some showed remarkable potencies. Importantly, tere- and isophthalamides derivatives belong to new structural classes of heparanase inhibitors and some of them showed enzyme affinities (61 and 63, IC(50) = 0.32 and 0.12 µM, respectively) similar to those of the most potent small-molecule inhibitors reported so far. Docking studies provided a comprehensive binding hypothesis shared by compounds with significant structural diversity. The most potent inhibitors reduced cell invasiveness and inhibited the expression of proangiogenic factors in tumour cell lines.