College of Pharmacy, Department of Medicinal Chemistry and Pharmacognosy , University of Illinois at Chicago , 833 South Wood Street , Chicago , Illinois 60612 , United States.
Department of Pharmacology, Toxicology & Neurology , Augusta University , 1459 Laney Walker Blvd , Augusta , Georgia 30912 , United States.
ACS Chem Neurosci. 2018 May 16;9(5):894-900. doi: 10.1021/acschemneuro.7b00435. Epub 2018 Jan 17.
Activation of HIF-1α and Nrf2 is a primary component of cellular response to oxidative stress, and activation of HIF-1α and Nrf2 provides neuroprotection in models of neurodegenerative disorders, including ischemic stroke, Alzheimer's and Parkinson's diseases. Screening a library of CNS-targeted drugs using novel reporters for HIF-1α and Nrf2 elevation in neuronal cells revealed histone deacetylase (HDAC) inhibitors as potential activators of these pathways. We report the identification of phenylhydroxamates as single agents exhibiting tripartite inhibition of HDAC6, inhibition of HIF-1 prolyl hydroxylase (PHD), and activation of Nrf2. Two superior tripartite agents, ING-6 and ING-66, showed neuroprotection against various cellular insults, associated with stabilization of both Nrf2 and HIF-1, and expression of their respective target genes in vitro and in vivo. Discovery of the innate ability of phenylhydroxamate HDAC inhibitors to activate Nrf2 and HIF provides a novel route to multifunctional neuroprotective agents and cautions against HDAC6 selective inhibitors as chemical probes of specific HDAC isoform function.
HIF-1α 和 Nrf2 的激活是细胞对氧化应激反应的主要组成部分，HIF-1α 和 Nrf2 的激活为包括缺血性中风、阿尔茨海默病和帕金森病在内的神经退行性疾病模型提供了神经保护作用。使用新型神经元细胞中 HIF-1α 和 Nrf2 升高的报告器，对中枢神经系统靶向药物文库进行筛选，发现组蛋白去乙酰化酶 (HDAC) 抑制剂是这些途径的潜在激活剂。我们报告了苯甲酰羟肟酸作为单一试剂的鉴定，其表现出对 HDAC6 的三部分抑制、对 HIF-1 脯氨酰羟化酶 (PHD) 的抑制和对 Nrf2 的激活。两种优越的三部分试剂 ING-6 和 ING-66 显示出对各种细胞损伤的神经保护作用，与 Nrf2 和 HIF-1 的稳定以及它们各自的靶基因在体外和体内的表达相关。苯甲酰羟肟酸 HDAC 抑制剂激活 Nrf2 和 HIF 的固有能力的发现为多功能神经保护剂提供了一条新途径，并告诫人们不要将 HDAC6 选择性抑制剂用作特定 HDAC 同工型功能的化学探针。
