Kinetically Selective Inhibitors of Histone Deacetylase 2 (HDAC2) as Cognition Enhancers.
Kinetically Selective Inhibitors of Histone Deacetylase 2 (HDAC2) as Cognition Enhancers.
复制标题
组蛋白脱乙酰酶 2 (HDAC2) 的动力学选择性抑制剂作为认知增强剂
DOI：
10.1039/c4sc02130d
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发表时间：
2015-01-01
期刊：
影响因子：
8.4
通讯作者：
Holson EB
中科院分区：
文献类型：
--
作者：
Wagner FF;Zhang YL;Fass DM;Joseph N;Gale JP;Weïwer M;McCarren P;Fisher SL;Kaya T;Zhao WN;Reis SA;Hennig KM;Thomas M;Lemercier BC;Lewis MC;Guan JS;Moyer MP;Scolnick E;Haggarty SJ;Tsai LH;Holson EB
HDAC2 的动力学选择性抑制剂可增强 CK-p25 神经退行性小鼠模型的学习和记忆能力。为了开发新型促智疗法来解决一系列脑部疾病常见的认知障碍，我们着手开发 HDAC2 的高选择性小分子抑制剂，HDAC2 是一种染色质修饰组蛋白脱乙酰酶，与记忆形成和突触可塑性有关。设计并评估了新型邻氨基苯胺抑制剂相对于其他 I 类 HDAC 选择性抑制 HDAC2 的能力。动力学和热力学结合特性是我们设计策略的基本要素，并且鉴定出两类新型邻氨基苯胺，它们对 HDAC2 与高度同源的异构体 HDAC1 表现出动力学选择性（停留时间有偏差）。这些动力学选择性 HDAC2 抑制剂（BRD6688 和 BRD4884）在原代小鼠神经细胞培养测定中，在神经退行性疾病模型 CK-p25 小鼠的海马中增加了 H4K12 和 H3K9 组蛋白乙酰化，并在认知行为模型中挽救了这些小鼠的相关记忆缺陷。这些研究首次证明，选择性药理学抑制 HDAC2 是可行的，并且抑制该酶的催化活性可以作为增强学习和记忆过程的治疗方法，而学习和记忆过程在许多神经和精神疾病中受到影响。
Kinetically selective inhibitors of HDAC2 enhanced learning and memory in a CK-p25 mouse model of neurodegeneration. Aiming towards the development of novel nootropic therapeutics to address the cognitive impairment common to a range of brain disorders, we set out to develop highly selective small molecule inhibitors of HDAC2, a chromatin modifying histone deacetylase implicated in memory formation and synaptic plasticity. Novel ortho-aminoanilide inhibitors were designed and evaluated for their ability to selectively inhibit HDAC2 versus the other Class I HDACs. Kinetic and thermodynamic binding properties were essential elements of our design strategy and two novel classes of ortho-aminoanilides, that exhibit kinetic selectivity (biased residence time) for HDAC2 versus the highly homologous isoform HDAC1, were identified. These kinetically selective HDAC2 inhibitors (BRD6688 and BRD4884) increased H4K12 and H3K9 histone acetylation in primary mouse neuronal cell culture assays, in the hippocampus of CK-p25 mice, a model of neurodegenerative disease, and rescued the associated memory deficits of these mice in a cognition behavioural model. These studies demonstrate for the first time that selective pharmacological inhibition of HDAC2 is feasible and that inhibition of the catalytic activity of this enzyme may serve as a therapeutic approach towards enhancing the learning and memory processes that are affected in many neurological and psychiatric disorders.