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

Frei, Matthias; Wirawan, Ricky; Wein, Thomas; Bracher, Franz

doi:10.3390/ijms26209855

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

Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University, Butenandtstr. 5–13, 81377 Munich, Germany

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Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2025, 26(20), 9855; https://doi.org/10.3390/ijms26209855

Submission received: 3 September 2025 / Revised: 5 October 2025 / Accepted: 8 October 2025 / Published: 10 October 2025

(This article belongs to the Section Molecular Biology)

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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.

Keywords: sirtuin 2 inhibitor; Sirt2 inhibitor; SirReal2; structure–activity relationship; hybridization strategy; highly potent and selective Sirt2 inhibitor; structural optimization

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MDPI and ACS Style

Frei, M.; Wirawan, R.; Wein, T.; Bracher, F. Lead Structure-Based Hybridization Strategy Reveals Major Potency Enhancement of SirReal-Type Sirt2 Inhibitors. Int. J. Mol. Sci. 2025, 26, 9855. https://doi.org/10.3390/ijms26209855

AMA Style

Frei M, Wirawan R, Wein T, Bracher F. Lead Structure-Based Hybridization Strategy Reveals Major Potency Enhancement of SirReal-Type Sirt2 Inhibitors. International Journal of Molecular Sciences. 2025; 26(20):9855. https://doi.org/10.3390/ijms26209855

Chicago/Turabian Style

Frei, Matthias, Ricky Wirawan, Thomas Wein, and Franz Bracher. 2025. "Lead Structure-Based Hybridization Strategy Reveals Major Potency Enhancement of SirReal-Type Sirt2 Inhibitors" International Journal of Molecular Sciences 26, no. 20: 9855. https://doi.org/10.3390/ijms26209855

APA Style

Frei, M., Wirawan, R., Wein, T., & Bracher, F. (2025). Lead Structure-Based Hybridization Strategy Reveals Major Potency Enhancement of SirReal-Type Sirt2 Inhibitors. International Journal of Molecular Sciences, 26(20), 9855. https://doi.org/10.3390/ijms26209855

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

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