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 IC50 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, IC50 = 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.

New classes of potent heparanase inhibitors from ligand-based virtual screening / Pala, D.; Scalvini, L.; Elisi, G. M.; Lodola, A.; Mor, M.; Spadoni, G.; Ferrara, F. F.; Pavoni, E.; Roscilli, G.; Milazzo, F. M.; Battistuzzi, G.; Rivara, S.; Giannini, G.. - In: JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY. - ISSN 1475-6366. - 35:1(2020), pp. 1685-1696. [10.1080/14756366.2020.1811701]

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

Pala D.;Scalvini L.;Elisi G. M.;Lodola A.;Mor M.;Rivara S.
;
2020-01-01

Abstract

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 IC50 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, IC50 = 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.
2020
New classes of potent heparanase inhibitors from ligand-based virtual screening / Pala, D.; Scalvini, L.; Elisi, G. M.; Lodola, A.; Mor, M.; Spadoni, G.; Ferrara, F. F.; Pavoni, E.; Roscilli, G.; Milazzo, F. M.; Battistuzzi, G.; Rivara, S.; Giannini, G.. - In: JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY. - ISSN 1475-6366. - 35:1(2020), pp. 1685-1696. [10.1080/14756366.2020.1811701]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2884877
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