8OWZ

Crystal structure of human Sirt2 in complex with a triazole-based SirReal

8OWZ の概要

• エントリーDOI: 10.2210/pdb8owz/pdb
• 分子名称: NAD-dependent protein deacetylase sirtuin-2, 2-(4,6-dimethylpyrimidin-2-yl)sulfanyl-N-[5-[[3-[[1-(2-methoxyethyl)-1,2,3-triazol-4-yl]methoxy]phenyl]methyl]-1,3-thiazol-2-yl]ethanamide, 1,2-ETHANEDIOL, ... (8 entities in total)
• 機能のキーワード: inhibitor, sirtuin 2, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 35680.99

構造登録者

Friedrich, F.,Zhang, L.,Schiedel, M.,Einsle, O.,Jung, M. (登録日: 2023-04-28, 公開日: 2023-11-15, 最終更新日: 2023-11-22)

主引用文献

Sinatra, L.,Vogelmann, A.,Friedrich, F.,Tararina, M.A.,Neuwirt, E.,Colcerasa, A.,Konig, P.,Toy, L.,Yesiloglu, T.Z.,Hilscher, S.,Gaitzsch, L.,Papenkordt, N.,Zhai, S.,Zhang, L.,Romier, C.,Einsle, O.,Sippl, W.,Schutkowski, M.,Gross, O.,Bendas, G.,Christianson, D.W.,Hansen, F.K.,Jung, M.,Schiedel, M.
Development of First-in-Class Dual Sirt2/HDAC6 Inhibitors as Molecular Tools for Dual Inhibition of Tubulin Deacetylation.
J.Med.Chem., 66:14787-14814, 2023

PubMed Abstract: Dysregulation of both tubulin deacetylases sirtuin 2 (Sirt2) and the histone deacetylase 6 (HDAC6) has been associated with the pathogenesis of cancer and neurodegeneration, thus making these two enzymes promising targets for pharmaceutical intervention. Herein, we report the design, synthesis, and biological characterization of the first-in-class dual Sirt2/HDAC6 inhibitors as molecular tools for dual inhibition of tubulin deacetylation. Using biochemical assays and cell-based methods for target engagement, we identified Mz325 () as a potent and selective inhibitor of both target enzymes. Inhibition of both targets was further confirmed by X-ray crystal structures of Sirt2 and HDAC6 in complex with building blocks of . In ovarian cancer cells, evoked enhanced effects on cell viability compared to single or combination treatment with the unconjugated Sirt2 and HDAC6 inhibitors. Thus, our dual Sirt2/HDAC6 inhibitors are important new tools to study the consequences and the therapeutic potential of dual inhibition of tubulin deacetylation.

PubMed: 37902787
DOI: 10.1021/acs.jmedchem.3c01385

実験手法

X-RAY DIFFRACTION (1.65 Å)