Structure-activity studies of 1,2,4-oxadiazoles for the inhibition of the NAD+ dependent lysine deacylase Sirtuin2

The NAD+-dependent lysine deacylase Sirtuin2 (Sirt2) is involved in multiple pathological conditions, including cancer. Targeting Sirt2 has thus received an increased interest for therapeutic purpose, including the ortholog from Schistosoma mansoni (SmSirt2) for the potential treatment of the neglected tropical disease schistosomiasis. We previously identified a 1,2,4-oxadiazole-based scaffold from the screening of the “Kinetobox” library as inhibitor of both human Sirt2 and SmSirt2. Herein, we describe structure-activity studies on 1,2,4-oxadiazole based analogs, which are potent inhibitors of Sirt2 deacetylation and demyristoylation. Docking experiments proposed a substrate competitive and co-factor non-competitive binding mode of inhibition, which could be confirmed in vitro via binding assays and kinetic analysis. Optimized analogs reduced cell viability and inhibited prostate cancer cell migration, in correlation with Sirt2 deacetylase inhibition both in vitro and in cells.The NAD+-dependent lysine deacylase Sirtuin2 (Sirt2) is involved in multiple pathological conditions, including cancer. Targeting Sirt2 has thus received an increased interest for therapeutic purpose, including the ortholog from Schistosoma mansoni (SmSirt2) for the potential treatment of the neglected tropical disease schistosomiasis. We previously identified a 1,2,4-oxadiazole-based scaffold from the screening of the “Kinetobox” library as inhibitor of both human Sirt2 and SmSirt2. Herein, we describe structure-activity studies on 1,2,4-oxadiazole based analogs, which are potent inhibitors of Sirt2 deacetylation and demyristoylation. Docking experiments proposed a substrate competitive and co-factor non-competitive binding mode of inhibition, which could be confirmed in vitro via binding assays and kinetic analysis. Optimized analogs reduced cell viability and inhibited prostate cancer cell migration, in correlation with Sirt2 deacetylase inhibition both in vitro and in cells.