Discovery and antitumor evaluation of novel inhibitors of spermine oxidase

Abstract Increasing knowledge of the relationship between cancer and dysregulated polyamine catabolism suggests interfering with aberrant polyamine metabolism for anticancer therapy that will have considerable clinical promise. SMO (spermine oxidase) plays an essential role in regulating the polyamines homeostasis. Therefore, development of SMO inhibitors has increasingly attracted much attention. Previously, we successfully purified and characterised SMO. Here, we presented an in silico drug discovery pipeline by combining pharmacophore modelling and molecular docking for the virtual screening of SMO inhibitors. In vitro evaluation showed that N-(3-{[3-(dimethylamino)propyl]amino}propyl)-8-quinolinecarboxamide (SI-4650) inhibited SMO enzyme activity, increased substrate spermine content and reduced product spermidine content, indicating that SI-4650 can interfere with polyamine metabolism. Furthermore, SI-4650 treatment suppressed cell proliferation and migration. Mechanistically, SI-4650 caused cell cycle arrest, induced cell apoptosis, and promoted autophagy. These results demonstrated the properties of interfering with polyamine metabolism of SI-4650 as a SMO inhibitor and the potential for cancer treatment