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

[Image: see text] 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 again...

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Detalles Bibliográficos
Autores principales: Leung, Leo, Niculescu-Duvaz, Dan, Smithen, Deborah, Lopes, Filipa, Callens, Cedric, McLeary, Robert, Saturno, Grazia, Davies, Lawrence, Aljarah, Mohammed, Brown, Michael, Johnson, Louise, Zambon, Alfonso, Chambers, Tim, Ménard, Delphine, Bayliss, Natasha, Knight, Ruth, Fish, Laura, Lawrence, Rae, Challinor, Mairi, Tang, HaoRan, Marais, Richard, Springer, Caroline
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2019
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937593/
https://www.ncbi.nlm.nih.gov/pubmed/31070916
http://dx.doi.org/10.1021/acs.jmedchem.9b00335
Descripción
Sumario:[Image: see text] 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 (IC(50)) 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.