Selisistat S-enantiomer (EX-527 S-enantiomer) is an effective and specific SIRT1 inhibitor (IC50 = 98 nM) and shows >200-fold selectivity against SIRT2/3.

SIRT1:98 nM

Treatment with Selisistat S-enantiomer dramatically increased acetylation at lysine 382 of p53 after different types of DNA damage in primary human mammary epithelial cells and several cell lines. Inhibition of SIRT1 catalytic activity by Selisistat S-enantiomer had no effect on cell growth, viability, or p53-controlled gene expression in cells treated with etoposide [1]. When the function of SIRT1 is inhibited by Selisistat S-enantiomer or its expression is suppressed by RNAi, the upregulated level and release of IL-1β and TNF-α by high glucose are further increased [2]. When HCT116 cells were cultured in 0.1% serum, addition of Selisistat S-enantiomer caused a 90% increase in cell number after 7 days. In the presence of 10% serum, Selisistat S-enantiomer did not change cell number in long term culture [3].

The central pretreatment with Selisistat S-enantiomer blunted the ghrelin-induced food intake in rats. Mice lacking p53, a target of SIRT1 action, failed to respond to ghrelin in feeding behavior. Ghrelin failed to phosphorylate hypothalamic AMPK when rats were pretreated with Selisistat S-enantiomer, as it did in p53 KO mice [4]. Selisistat S-enantiomer abolished RSV-induced attenuation of microvascular inflammation in ob/ob septic mice [5].