Details

Autor(en) / Beteiligte

• Hajdú, István
• Kardos, József
• Major, Balázs
• Fabó, Gabriella
• Lőrincz, Zsolt
• Cseh, Sándor
• Dormán, György

Titel

Inhibition of the LOX enzyme family members with old and new ligands. Selectivity analysis revisited

Ist Teil von

• Bioorganic & medicinal chemistry letters, 2018-10, Vol.28 (18), p.3113-3118

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2018

Quelle

MEDLINE

Beschreibungen/Notizen

• [Display omitted] •Fluorometric activity assay developed for LOX enzyme family members.•The activity profile of known pan-inhibitor molecules revisited.•Small targeted library generated by 2D ligand-based chemoinformatics methods.•Ten hits (10.4% hit rate) identified with distinct subfamily activity profiles.•Potential inhibitors identified for LOXL3 and LOXL4, emerging drug targets in cancer. 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.