TY  - JOUR
AU  - Wirawan, Ricky
AU  - Frei, Matthias
AU  - Heider, Anna
AU  - Papenkordt, Niklas
AU  - Friedrich, Florian
AU  - Wein, Thomas
AU  - Jung, Manfred
AU  - Groll, Michael
AU  - Huber, Eva
AU  - Bracher, Franz
TI  - Tailored SirReal-type inhibitors enhance SIRT2 inhibition through ligand stabilization and disruption of NAD<sup>+</sup> co-factor binding
JO  - RSC medicinal chemistry
VL  - 16
IS  - 11
SN  - 2040-2503
CY  - Cambridge
PB  - Royal Society of Chemistry
M1  - PUBDB-2025-04028
SP  - 5419 - 5440
PY  - 2025
N1  - ISSN 2632-8682 not unique: **2 hits**.
AB  - Human sirtuin 2 (SIRT2) is an NAD+ dependant enzyme that has been linked to the pathogenesis of various diseases, making it a promising target for pharmaceutical intervention. This study presents a systematic investigation on the inhibitory effects of SIRT2 inhibitors functionalized with diverse electrophilic functional groups. Guided by initial docking studies, we designed and synthesised 14 derivatives of two published potent lead structures 24a and SirReal2. The most potent and subtype selective SIRT2 inhibitor 29 (RW-78) exhibits an IC50 of 26 nM, which outperforms its lead structure 24a (IC50 = 79 nM) by a factor of 3. The increased potency of 29 is explained by halogen–π interactions with SIRT2 residues as visualized by X-ray crystallography. Furthermore, 29 interferes with NAD+ binding, highlighting co-factor displacement as a valid strategy to inhibit SIRT2. Additionally, we showed cellular target engagement via NanoBRET assays in HEK293T cells (EC50 = 15 nM). Altogether our findings provide a deeper insight into the structure–activity relationships of these SirReal-type inhibitors and offer new avenues for optimisation of SIRT2 inhibitors.
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1039/D5MD00144G
UR  - https://bib-pubdb1.desy.de/record/638310
ER  -