Target: Sirtuin 2 (Sirt2)
IC50: 140 nM
SirReal2 is a potent and selective Sirtuin 2 (Sirt2) inhibitor with IC50 value of 140 nM [1]. The Sirtuins are a highly conserved class of NAD+-dependent lysine deacylases. The human isotype Sirtuin 2 (Sirt2) deacetylates both cytoplasmatic and nuclear proteins and it has been implicated in the pathogenesis of cancer, neurodegeneration, and inflammation [1, 2]. Therefore, the modulation of Sirt2 activity is a promising strategy for pharmaceutical intervention.
In vitro: SirReal2, the most potent Sirtuin-rearranging ligand, induced the checkpoint protein BubR1 destabilization and hyperacetylation of the microtubule network in HeLa cells [1]. Moreover, SirReal2 (20 μM) inhibited Sirt2 activity but was unable to affect the activity of the other Class-I sirtuins Sirt1 and Sirt3 in cells. SirReal2 (12.5, 25, and 50 μM) treatment dose-dependently induced depletion of BubR1 but did not alter cell cycle distribution [1].
In vivo: SirReal2 (12.5, 25, and 50 μM) treatment did not induce the increase in acetylation of p53 [1].
References:
1. Rumpf T, Schiedel M, Karaman B, Roessler C, North BJ, Lehotzky A, et al. Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. Nat Commun. 2015;6:6263. Epub 2015/02/13.
2. Galleano I, Schiedel M, Jung M, Madsen AS, Olsen CA. A Continuous, Fluorogenic Sirtuin 2 Deacylase Assay: Substrate Screening and Inhibitor Evaluation. J Med Chem. 2016;59(3):1021-31. Epub 2016/01/21.