Lead Structure‐Based Hybridization Strategy Reveals Major Potency Enhancement of SirReal‐Type Sirt2 Inhibitors

Selective and potent inhibitors of the NAD+-dependent deacetylase Sirt2 represent a valuable epigenetic approach for the treatment of hitherto incurable diseases such as Parkinson's disease, Huntington’s disease, Alzheimer's disease and multiple sclerosis. Guided by docking studies, a lead structure-based hybridization concept was developed, resulting in a series of very effective Sirt2 inhibitors. With RW-93 we present a highly potent and selective Sirt2 inhibitor (IC50 = 16 nM), which as a next generation SirReal-type inhibitor significantly surpasses established Sirt2 inhibitors and extends current structure-activity relationships. The structural modification strategy employed in this study proved to be a highly promising approach, resulting in the identification of the most potent low-molecular Sirt2 inhibitors reported to date.