Inhibition of the LOX enzyme family members with old and new ligands. Selectivity analysis revisited |
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Authors: | István Hajdú József Kardos Balázs Major Gabriella Fabó Zsolt L?rincz Sándor Cseh György Dormán |
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Institution: | 1. TargetEx Ltd., Madách Imre utca 31/2, H-2120 Dunakeszi, Hungary;2. Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok körútja 2, H-1117 Budapest, Hungary;3. Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117 Budapest, Hungary |
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Abstract: | Lysyl oxidase (LOX) enzymes as potential drug targets maintain constant attention in the therapy of fibrosis, cancer and metastasis. In order to measure the inhibitory activity of small molecules on the LOX enzyme family members a fluorometric activity screening method was developed. During assay validation, previously reported non-selective small inhibitor molecules (BAPN, MCP-1, thiram, disulfiram) were investigated on all of the major LOX enzymes. We confirmed that MCP-1, thiram, disulfiram are in fact pan-inhibitors, while BAPN inhibits only LOX-like enzymes (preferably LOX-like-protein-2, LOXL2) in contrast to the previous reports. We measured the LOX inhibitory profile of a small targeted library generated by 2D ligand-based chemoinformatics methods. Ten hits (10.4% hit rate) were identified, and the compounds showed distinct activity profiles. Potential inhibitors were also identified for LOX-like-protein-3 (LOXL3) and LOX-like-protein-4 (LOXL4), that are considered as emerging drug targets in the therapy of melanoma and gastric cancer. |
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Keywords: | Lysyl oxidase Fluorescent LOX assay 2D ligand-based virtual screening LOX targeted library Novel LOX family inhibitors |
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