<br>开发一流的双 SIRT2/HDAC6 抑制剂作为双重抑制微管蛋白脱乙酰化的分子工具,Journal of Medicinal Chemistry

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开发一流的双 SIRT2/HDAC6 抑制剂作为双重抑制微管蛋白脱乙酰化的分子工具
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-10-30 , DOI: 10.1021/acs.jmedchem.3c01385
Laura Sinatra ₁ , Anja Vogelmann ₂ , Florian Friedrich ₂ , Margarita A Tararina ₃ , Emilia Neuwirt _{4,

5} , Arianna Colcerasa ₂ , Philipp König ₆ , Lara Toy ₇ , Talha Z Yesiloglu ₈ , Sebastian Hilscher _{8,

9} , Lena Gaitzsch ₂ , Niklas Papenkordt ₂ , Shiyang Zhai ₆ , Lin Zhang ₁₀ , Christophe Romier ₁₁ , Oliver Einsle ₁₀ , Wolfgang Sippl ₈ , Mike Schutkowski ₉ , Olaf Gross _{4,

5,

12} , Gerd Bendas ₆ , David W Christianson ₃ , Finn K Hansen _{1,

6} , Manfred Jung ₂ , Matthias Schiedel _{7,

13}

Affiliation

Institute for Drug Discovery, Medical Faculty, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany.
Institute of Pharmaceutical Sciences, University of Freiburg, Albertstraße 25, 79104 Freiburg, Germany.
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
Institute of Neuropathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Breisacherstraße 64, 79106 Freiburg, Germany.
CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Schänzlestraße 18, 79104 Freiburg, Germany.
Department of Pharmaceutical & Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander-University Erlangen-Nürnberg, Nikolaus-Fiebiger-Straße 10, 91058 Erlangen, Germany.
Department of Medicinal Chemistry, Institute of Pharmacy, Martin-Luther University of Halle-Wittenberg, Wolfgang-Langenbeck-Straße 2-4, 06120 Halle (Saale), Germany.
Department of Enzymology, Charles Tanford Protein Center, Institute of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, 06120 Halle, Germany.
Institute of Biochemistry, University of Freiburg, Albertstraße 21, 79104 Freiburg, Germany.
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg, CNRS UMR 7104, Inserm UMR-S 1258, 1 rue Laurent Fries, F-67400 Illkirch, France.
Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Breisacherstraße 64, 79106 Freiburg, Germany.
Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany.

微管蛋白脱乙酰酶 sirtuin 2 （Sirt2）和组蛋白脱乙酰酶 6 （HDAC6）的失调与癌症和神经退行性的发病机制有关，因此使这两种酶成为药物干预的有希望的靶点。在此，我们报道了一流的双重 Sirt2/HDAC6 抑制剂的设计、合成和生物学表征，作为双重抑制微管蛋白脱乙酰化的分子工具。使用生化体外测定和基于细胞的靶标结合方法，我们确定 Mz325 （33）是两种靶酶的有效选择性抑制剂。Sirt2 和 HDAC6 的 X 射线晶体结构与 33 个构建单元的复合物进一步证实了对这两个靶标的抑制。在卵巢癌细胞中，与使用未偶联的 Sirt2 和 HDAC6 抑制剂的单独或联合治疗相比，33 对细胞活力的影响增强。因此，我们的双重 Sirt2/HDAC6 抑制剂是研究微管蛋白脱乙酰双重抑制的后果和治疗潜力的重要新工具。

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更新日期：2023-10-30

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