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 and targeting Sirt2 has thus received an increased interest for therapeutic purpose. Furthermore, addressing the ortholog from Schistosoma mansoni (SmSirt2) has been considered 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 a dual inhibitor of human Sirt2 and SmSirt2. Herein, we describe structure-activity studies on 1,2,4-oxadiazole based analogs, which are potent inhibitors of human Sirt2 deacetylation. As proposed by docking studies, a substrate competitive and co-factor non-competitive binding mode of inhibition could be determined in vitro via binding assays and kinetic analysis, and further confirmed by a crystal structure of an oxadiazole inhibitor in complex with hSirt2. Optimized analogs reduced cell viability and inhibited prostate cancer cell migration, in correlation with Sirt2 deacetylase inhibition both in vitro and in cells.