New classes of potent heparanase inhibitors from ligand-based virtual screening. (1st January 2020)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Journal of enzyme inhibition and medicinal chemistry. Volume 35:Number 1(2020)
• Page Start: 1685
• Page End: 1696
• Publication Date: 2020-01-01
• Subjects: Heparanase -- heparan sulphate -- virtual screening; Enzyme inhibitors -- Periodicals; Enzyme Inhibitors -- periodicals; Biochemistry -- periodicals; 572.7
• DOI: 10.1080/14756366.2020.1811701
• Languages: English
• ISSNs: 1475-6366

Abstract

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.