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

Leo Man Ho Leung, Dan Niculescu-Duvaz, Deborah Smithen, Filipa Lopes, Cedric Callens, Robert Mcleary, Grazia Saturno, Lawrence Davies, Mohammed Aljarah, Michael Brown, Raelene Lawrence, Mairi Challinor, Haoran Tang, Richard Marais, Caroline Springer

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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.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Publication statusPublished - 27 Jun 2019

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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