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

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.