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

## TL;DR

Researchers developed a new strategy to create highly potent Sirt2 inhibitors, which could help treat diseases like Parkinson's and Alzheimer's.

## Contribution

A lead structure-based hybridization strategy was used to significantly enhance the potency of Sirt2 inhibitors.

## Key findings

- RW-93 is a highly potent Sirt2 inhibitor with an IC50 of 16 nM.
- The strategy identified the most potent low-molecular-weight Sirt2 inhibitor reported to date.
- The method contributes to the extension of the current structure-activity relationship profile for Sirt2 inhibitors.

## Abstract

Selective and potent inhibitors of the NAD+-dependent deacetylase Sirt2 represent a valuable epigenetic strategy for the treatment of currently incurable diseases such as Parkinson’s disease, Huntington’s disease, Alzheimer’s disease, and multiple sclerosis. Guided by molecular docking and MM/GBSA validation studies, a lead structure-based hybridization strategy was developed, resulting in a series of very effective Sirt2 inhibitors. With RW-93, we present a highly potent and subtype selective Sirt2 inhibitor (IC50 = 16 nM), which as a next generation SirReal-type inhibitor significantly surpasses established Sirt2 inhibitors and contributes to the extension of the current SAR profile. The structural modification strategy employed in this study proved to be highly promising, resulting in the identification of the most potent low-molecular-weight Sirt2 inhibitor reported to date, providing a promising target for further medicinal chemistry-driven SAR studies.