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

István Hajdú, J. Kardos, Balázs Major, Gabriella Fabó, Zsolt Lőrincz, S. Cseh, György Dormán

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
JournalBioorganic and Medicinal Chemistry Letters
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Protein-Lysine 6-Oxidase
Ligands
Enzymes
Aminopropionitrile
Thiram
Disulfiram
Proteins
Molecules
Inhibition (Psychology)
Pharmaceutical Preparations
Libraries
Stomach Neoplasms
Melanoma
Assays
Screening
Fibrosis
Neoplasm Metastasis

Keywords

  • 2D ligand-based virtual screening
  • Fluorescent LOX assay
  • LOX targeted library
  • Lysyl oxidase
  • Novel LOX family inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Inhibition of the LOX enzyme family members with old and new ligands. Selectivity analysis revisited. / Hajdú, István; Kardos, J.; Major, Balázs; Fabó, Gabriella; Lőrincz, Zsolt; Cseh, S.; Dormán, György.

In: Bioorganic and Medicinal Chemistry Letters, 01.01.2018.

Research output: Contribution to journalArticle

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