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
  • 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.