Publications by authors named "Natasha Bayliss"

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

J Med Chem 2019 06 23;62(12):5863-5884. Epub 2019 May 23.

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

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) 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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June 2019