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

J Med Chem. 2019 Jun 27;62(12):5863-5884. doi: 10.1021/acs.jmedchem.9b00335.

Leo Leung ¹, Dan Niculescu-Duvaz ¹, Deborah Smithen ¹, Filipa Lopes ¹, Cedric Callens ¹, Robert McLeary ¹, Grazia Saturno, Lawrence Davies ¹, Mohammed Aljarah ¹, Michael Brown ¹, Louise Johnson ¹, Alfonso Zambon ¹, Tim Chambers, Delphine Ménard ¹, Natasha Bayliss ¹, Ruth Knight ¹, Laura Fish ¹, Rae Lawrence, Mairi Challinor, HaoRan Tang, Richard Marais, Caroline Springer ¹

Affiliations

Affiliation

1 Cancer Research UK Centre for Cancer Therapeutics , The Institute of Cancer Research , 15 Cotswold Road , London SM2 5NG , United Kingdom.

PMID: 31070916 DOI: 10.1021/acs.jmedchem.9b00335

Abstract

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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