9S46Summary for 9S46
| Entry DOI | 10.2210/pdb9s46/pdb |
| Related | 5YQO 9S44 |
| Descriptor | NAD-dependent protein deacetylase sirtuin-2, ~{N}-[2-chloranyl-4-[[3-[2-(4,6-dimethylpyrimidin-2-yl)sulfanylethanoylamino]phenyl]methoxy]phenyl]-1-methyl-pyrazole-4-carboxamide, ZINC ION, ... (5 entities in total) |
| Functional Keywords | inhibitior, lysine deacetylase, nad+-dependant enzyme, epigenetics, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 35152.26 |
| Authors | Wirawan, R.,Frei, M.,Heider, A.,Papenkordt, N.,Friedrich, F.,Wein, T.,Jung, M.,Groll, M.,Huber, E.M.,Bracher, F. (deposition date: 2025-07-25, release date: 2025-08-20, Last modification date: 2025-11-26) |
| Primary citation | Wirawan, R.,Frei, M.,Heider, A.,Papenkordt, N.,Friedrich, F.,Wein, T.,Jung, M.,Groll, M.,Huber, E.M.,Bracher, F. Tailored SirReal-type inhibitors enhance SIRT2 inhibition through ligand stabilization and disruption of NAD + co-factor binding. Rsc Med Chem, 16:5419-5440, 2025 Cited by PubMed Abstract: 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 IC of 26 nM, which outperforms its lead structure 24a (IC = 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 NanoBRET assays in HEK293T cells (EC = 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. PubMed: 40919320DOI: 10.1039/d5md00144g PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.45 Å) |
Structure validation
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