Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, District of Columbia 20052, United States.
Department of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois 60612, United States.
J Med Chem. 2020 Sep 24;63(18):10246-10262. doi: 10.1021/acs.jmedchem.0c00567. Epub 2020 Sep 2.
Selective inhibition of histone deacetylase 6 (HDAC6) is being recognized as a therapeutic approach for cancers. In this study, we designed a new HDAC6 inhibitor, named Suprastat, using simulations. X-ray crystallography and molecular dynamics simulations provide strong evidence to support the notion that the aminomethyl and hydroxyl groups in the capping group of Suprastat establish significant hydrogen bond interactions, either direct or water-mediated, with residues D460, N530, and S531, which play a vital role in regulating the deacetylase function of the enzyme and which are absent in other isoforms. characterization of Suprastat demonstrates subnanomolar HDAC6 inhibitory potency and a hundred- to a thousand-fold HDAC6 selectivity over the other HDAC isoforms. studies reveal that a combination of Suprastat and anti-PD1 immunotherapy enhances antitumor immune response, mediated by a decrease of protumoral M2 macrophages and increased infiltration of antitumor CD8+ effector and memory T-cells.
组蛋白去乙酰化酶 6（HDAC6）的选择性抑制作用正被认为是癌症的一种治疗方法。在这项研究中，我们使用模拟设计了一种新的 HDAC6 抑制剂，命名为 Suprastat。X 射线晶体学和分子动力学模拟为以下观点提供了强有力的证据支持：即 Suprastat 封端基团中的氨甲基和羟基与残基 D460、N530 和 S531 建立了显著的氢键相互作用，无论是直接的还是通过水介导的，这些残基在调节酶的去乙酰化酶功能方面发挥着至关重要的作用，而在其他同工酶中则不存在。Suprastat 的特性研究表明，它对 HDAC6 的抑制作用具有亚纳摩尔级的效力，对其他 HDAC 同工酶的选择性则高达 100 至 1000 倍。研究表明，Suprastat 与抗 PD1 免疫疗法的联合使用增强了抗肿瘤免疫反应，其介导机制是减少促肿瘤 M2 巨噬细胞的浸润，并增加抗肿瘤 CD8+效应器和记忆 T 细胞的浸润。
