| Autor: |
Pala D; Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parma, Italy., Scalvini L; Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parma, Italy., Elisi GM; Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parma, Italy., Lodola A; Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parma, Italy., Mor M; Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parma, Italy., Spadoni G; Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino 'Carlo Bo', Urbino, Italy., Ferrara FF; Takis s.r.l., Roma, Italy., Pavoni E; Takis s.r.l., Roma, Italy., Roscilli G; Takis s.r.l., Roma, Italy., Milazzo FM; R&D Alfasigma S.p.A., Roma, Italy., Battistuzzi G; R&D Alfasigma S.p.A., Roma, Italy., Rivara S; Dipartimento di Scienze degli Alimenti e del Farmaco, Università degli Studi di Parma, Parma, Italy., Giannini G; R&D Alfasigma S.p.A., Roma, Italy. |
| Abstrakt: |
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. |
