Anti-metastatic Inhibitors of Lysyl Oxidase (LOX): Design and Structure-Activity Relationships

Research output: Contribution to journalArticle

  • External authors:
  • Leo Man Ho Leung
  • Dan Niculescu-Duvaz
  • Deborah Smithen
  • Filipa Lopes
  • Cedric Callens
  • Robert Mcleary
  • Grazia Saturno
  • Lawrence Davies
  • Mohammed Aljarah
  • Raelene Lawrence
  • Mairi Challinor
  • Haoran Tang
  • Caroline Springer


Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase that crosslinks collagens and elastin in the extracellular matrix (ECM) and is a critical mediator of tumor growth and metastatic spread. LOX is a target for cancer therapy and thus the search for therapeutic agents against LOX has been widely sought. We report herein the medicinal chemistry discovery of a series of LOX inhibitors bearing an aminomethylenethiophene (AMT) scaffold. High throughput screening (HTS) provided the initial hits. Structure-activity relationship (SAR) studies led to the discovery of AMT inhibitors with sub-micromolar half maximal inhibitory concentrations (IC50) in a LOX enzyme activity assay. Further SAR optimization yielded the orally bioavailable LOX inhibitor CCT365623 with good anti-LOX potency, selectivity, pharmacokinetic properties, as well as anti-metastatic efficacy.

Bibliographical metadata

Original languageEnglish
JournalJournal of Medicinal Chemistry
Publication statusAccepted/In press - 9 May 2019