Małecki Piotr H, Rüger Nicole, Roatsch Martin, Krylova Oxana, Link Andreas, Jung Manfred, Heinemann Udo, Weiss Manfred S
Macromolecular Crystallography, Helmholtz-Zentrum Berlin für Materialien und Energie, Albert-Einstein-Str. 15, 12489, Berlin, Germany.
Macromolecular Structure and Interaction, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125, Berlin, Germany.
ChemMedChem. 2019 Nov 6;14(21):1828-1839. doi: 10.1002/cmdc.201900441. Epub 2019 Oct 10.
Human histone demethylases are known to play an important role in the development of several tumor types. Consequently, they have emerged as important medical targets for the treatment of human cancer. Herein, structural studies on tetrazolylhydrazide inhibitors as a new scaffold for a certain class of histone demethylases, the JmjC proteins, are reported. A series of compounds are structurally described and their respective binding modes to the KDM4D protein, which serves as a high-resolution model to represent the KDM4 subfamily in crystallographic studies, are examined. Similar to previously reported inhibitors, the compounds described herein are competitors for the natural KDM4 cofactor, 2-oxoglutarate. The tetrazolylhydrazide scaffold fills an important gap in KDM4 inhibition and newly described, detailed interactions of inhibitor moieties pave the way to the development of compounds with high target-binding affinity and increased membrane permeability, at the same time.
已知人类组蛋白去甲基化酶在多种肿瘤类型的发展中发挥重要作用。因此，它们已成为治疗人类癌症的重要医学靶点。本文报道了关于四唑酰肼抑制剂作为一类组蛋白去甲基化酶（JmjC蛋白）新支架的结构研究。对一系列化合物进行了结构描述，并研究了它们与KDM4D蛋白各自的结合模式，KDM4D蛋白在晶体学研究中作为代表KDM4亚家族的高分辨率模型。与先前报道的抑制剂类似，本文所述化合物是天然KDM4辅因子2-氧代戊二酸的竞争者。四唑酰肼支架填补了KDM4抑制方面的一个重要空白，新描述的抑制剂部分的详细相互作用为同时开发具有高靶点结合亲和力和增加膜通透性的化合物铺平了道路。
