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

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posted on 2019-05-09, 00:00 authored by Leo Leung, Dan Niculescu-Duvaz, Deborah Smithen, Filipa Lopes, Cedric Callens, Robert McLeary, Grazia Saturno, Lawrence Davies, Mohammed Aljarah, Michael Brown, Louise Johnson, Alfonso Zambon, Tim Chambers, Delphine Ménard, Natasha Bayliss, Ruth Knight, Laura Fish, Rae Lawrence, Mairi Challinor, HaoRan Tang, Richard Marais, Caroline Springer
Lysyl oxidase (LOX) is a secreted copper-dependent amine oxidase that cross-links collagens and elastin in the extracellular matrix 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 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.

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