组蛋白去乙酰化酶抑制剂的研究进展

组蛋白是真核生物核染色体的重要组成部分。它们被分为五类(H,H2A,H2B,H3和H4),两组:核心组蛋白(H2A,H2B,H3和H4)和联结子组蛋白(H1)[1]。由组蛋白修饰所造成的染色体局部构象的改变,在真核生物基因表达调控中发挥着举足轻重的作用[2]。     

组蛋白去乙酰化酶 6 及其选择性抑制剂的研究进展

组蛋白去乙酰化酶 6(HDAC6)是组蛋白去乙酰化酶(HDACs)IIb 家族中的一员,主要催化 α- 微管蛋白、热休克蛋白 Hsp90、皮质肌动蛋白及过氧化物还原酶等的去乙酰化。HDAC6 与肿瘤、神经退行性疾病、炎症、自身免疫应答、细菌感染及心脏病等 诸多疾病的病理生理进程密切相关,是一个极具应用前景的药物靶标。选择性 HDAC6 抑制剂是目前该领域的研究热点,有望克服广谱 HDAC 抑制剂存在的选择性差、副作用大等缺点。综述 HDAC6 的结构、生化功能、与疾病的关系及其选择性抑制剂的研究进展,为开发 新型选择性 HDAC6 抑制剂提供参考。     

组蛋白去乙酰化酶抑制剂在乳腺癌方面的研究进展

乳腺癌是威胁女性生命的最常见肿瘤,它的发生和转移严重影响了患者的生存和生活状况.研究表明,组蛋白去乙酰化酶(HDAC)可以调节体内组蛋白乙酰化和去乙酰化的平衡,它的过度表达与乳腺癌的发生、发展密切相关.而组蛋白去乙酰化酶抑制剂(HDACi)对HDAC的抑制作用为肿瘤的治疗带来曙光,成为近年来研究的热门话题.该文通过对多...     

组蛋白去乙酰化酶4与人类疾病北大核心CSCD

组蛋白去乙酰化酶4(histone deacetylase 4,HDAC4)是一类依赖锌的去乙酰化酶,属于Ⅱ类组蛋白去乙酰化酶(histone deacetylases,HDACs),主要具有去乙酰化酶的活性。HDAC4由去乙酰化酶结构域发挥去乙酰化酶的作用,还具有核定位序列和核输出序列,通过转录后与翻译后水平的修饰可在细胞核和细胞质之间穿梭,进而参与多种调节过程。近年来的研究发现,HDAC4可参与基因的转录调控、细胞凋亡、代谢等诸多生物进程,在多种疾病的发生发展中发挥重要作用。本文主要从HDAC4的结构、去乙酰作用、自身的修饰及其在核浆中的穿梭作用对其进行概述,同时对其在骨关节炎、心血管疾病、肌萎缩性侧索硬化症等不同疾病中的作用、相关的分子机制及组蛋白抑制剂在肿瘤中的应用等方面的研究进展进行综述。     

组蛋白去乙酰化酶抑制剂调控缺血性脑卒中的分子机制

缺血性脑卒中（ischemic stroke,IS）约占所有卒中病例的80%,是全球范围内导致死亡和长期残疾的主要神经系统疾病,其核心病理机制为脑血流中断导致的神经细胞坏死和脑组织缺血性损伤,涉及细胞凋亡、炎症反应及氧化应激等多重分子过程。组蛋白去乙酰化酶（histone deacetylase,HDAC）通过去除组蛋白上的乙酰基团（acetyl group,Ac）调控染色质构象与基因表达,在神经细胞存活、炎症反应调控及血脑屏障稳态调节中发挥重要的作用。组蛋白去乙酰化酶抑制剂（HDAC inhibitor,HDACi）可抑制HDAC的活性,HDACi不仅作用于组蛋白,还可作用于热休克转录因子1（HSF1）、分子伴侣热休克蛋白90（HSP90）及细胞骨架蛋白α微管蛋白（α-tubulin）在内的多种非组蛋白,进而调控下游基因转录及相关信号通路,在IS模型中表现出显著神经保护作用。本文系统综述HDACs的分类、HDACi的作用机制,及其在IS后细胞凋亡抑制、神经炎症调控、血脑屏障修复及认知功能改善中的多重效应,同时探讨HDACi的靶向策略与临床应用前景,为HDACi治疗IS提供了新的理论依据与科学的研究方向。     

组蛋白去乙酰化酶4与人类疾病

组蛋白去乙酰化酶4（histone deacetylase 4,HDAC4）是一类依赖锌的去乙酰化酶,属于Ⅱ类组蛋白去乙酰化酶（histone deacetylases,HDACs）,主要具有去乙酰化酶的活性。HDAC4由去乙酰化酶结构域发挥去乙酰化酶的作用,还具有核定位序列和核输出序列,通过转录后与翻译后水平的修饰可在细胞核和细胞质之间穿梭,进而参与多种调节过程。近年来的研究发现,HDAC4可参与基因的转录调控、细胞凋亡、代谢等诸多生物进程,在多种疾病的发生发展中发挥重要作用。本文主要从HDAC4的结构、去乙酰作用、自身的修饰及其在核浆中的穿梭作用对其进行概述,同时对其在骨关节炎、心血管疾病、肌萎缩性侧索硬化症等不同疾病中的作用、相关的分子机制及组蛋白抑制剂在肿瘤中的应用等方面的研究进展进行综述。     

组蛋白去乙酰化酶抑制剂在急性髓系白血病中的应用

急性髓系白血病（AML）是造血干/祖细胞恶性克隆性疾病,以骨髓、血液和其他组织中髓系起源的异常原始细胞增殖为特征。“3+7”诱导方案（蒽环类药物联合阿糖胞苷）一直是治疗AML的基石,但仍有部分AML患者无法耐受强化疗或完全缓解后复发,目前AML的总体疗效仍不乐观。因此,寻找新药物以提高AML患者疗效具有重要的临床意义。越来越多的研究证明,表观遗传对AML的发生、发展起重要作用。组蛋白去乙酰化酶抑制剂（HDACi）是表观遗传修饰的分子靶向药物,可抑制组蛋白去乙酰化酶（HDAC）的活性,上调组蛋白赖氨酸的乙酰化水平,目前已应用于AML临床研究中,在联合治疗中显现出良好的耐受性与治疗效果。本综述介绍了HDAC和HDACi的分类依据以及在临床上的应用,阐述了伏立诺他、贝利司他、帕比司他、戊丙酸、恩替诺特、西达本胺等6种HDACi在AML中的临床前研究结果和临床应用研究进展,讨论了HDACi与其他抗癌药物联用在AML中的作用机制,并对HDACi今后的发展提出了建议,期望为临床治疗AML提供参考。     

运动调节组蛋白去乙酰化改善阿尔茨海默病的研究进展

阿尔茨海默病(Alzheimer’s disease,AD)是以渐进性认知功能障碍和记忆损害为主要特征的神经退行性疾病,是一种严重威胁老年人身心健康的中枢神经系统疾病。AD发病机制复杂,已有的研究发现,组蛋白去乙酰化参与调节AD的病理进程。运动作为一种行之有效的非药物干预手段对预防和延缓AD的发生具有重要作用。为此,本文综述了组蛋白去乙酰化在AD发病中的作用及其在运动缓解AD中的作用机制。     

组蛋白去乙酰化酶1/2参与调控小鼠卵子发生的研究进展

卵子发生是雌性哺乳动物的基本生殖过程,是后续受精及胚胎发育的基础.近年来研究表明,表观修饰在调控哺乳动物生殖过程(如卵子发生、精子发生、植入前胚胎发育及性别分化等)中扮演着重要的角色.以组蛋白乙酰化为例,组蛋白乙酰转移酶(histone acetyltransferases,HATs)和去乙酰化酶(histone de...     

组蛋白去乙酰化酶抑制剂诱导肿瘤细胞凋亡的机制

组蛋白去乙酰化酶抑制剂（HDACi）是一类新的化疗药物,能够有效抑制组蛋白去乙酰化酶的活性,促进组蛋白及非组蛋白的乙酰化修饰,在转录和翻译后修饰水平调控肿瘤靶蛋白及凋亡相关蛋白的表达和降解,活化凋亡信号通路,诱导肿瘤细胞凋亡。HDACi抑制抗氧化蛋白的表达,提高细胞内活性氧的水平,引起细胞的氧化损伤。因此,氧化损伤诱导的细胞凋亡也是HDACi杀伤肿瘤细胞的重要机制。HDACi诱导细胞凋亡机制的发现将进一步促进HDACi在临床治疗中的应用。     

Inhibition of histone deacetylase activity is a novel function of the antifolate drug methotrexate

Methotrexate (MTX) is a dihydrofolate reductase (DHFR) inhibitor widely used for treating human cancers, and overexpression of histone deacetylase (HDAC) is usually found in tumors. HDAC inhibitors (HDACi) can reactivate tumor suppressor genes and serve as potential anti-cancer drugs. In this study, we found that MTX shared structural similarity with some HDACi and molecular modeling showed that MTX indeed docks into the active site of HDLP, a bacterial homologue of HDAC. Subsequent in vitro assay demonstrated MTX’s inhibition on HDAC activity in human cancer cells. The global acetylation of histone H3 was also induced by MTX. Moreover, MTX inhibited immunoprecipitated HDAC1/2 activity but not their protein levels. This study provides evidence that MTX inhibits HDAC activity.     

Design and synthesis of novel and highly-active pan-histone deacetylase (pan-HDAC) inhibitors

Histone deacetylase (HDAC) inhibitions are known to elicit anticancer effects. We designed and synthesized several HDAC inhibitors. Among these compounds, compound 40 exhibited a more than 10-fold stronger inhibitory activity compared with that of suberoylanilide hydroxamic acid (SAHA) against each human HDAC isozyme in vitro (IC₅₀ values of 40: HDAC1, 0.0038 μM; HDAC2, 0.0082 μM; HDAC3, 0.015 μM; HDAC8, 0.0060 μM; HDAC4, 0.058 μM; HDAC9, 0.0052 μM; HDAC6, 0.058 μM). The dose of the administered HDAC inhibitors that contain hydroxamic acid as the zinc-binding group may be reduced by 40. Because the carbostyril subunit is a time-tested structural component of drugs and biologically active compounds, 40 most likely exhibits good absorption, distribution, metabolism, excretion, and toxicity (ADMET). Thus, compound 40 is expected to be a promising therapeutic agent or chemical tool for the investigation of life process.     

Inhibition of histone deacetylase1 induces autophagy

Autophagy is a process where cytoplasmic materials are degraded by lysosomal machinery. Histone deacetylase (HDAC) inhibitors induce autophagy, and HDAC6, one of class II HDAC isotypes, is directly involved in autophagic degradation in the cell. However, it is unclear if class I HDAC isotype such as HDCA1 is involved in this process. To investigate if class I HDAC isotype is involved in autophagy, a specific class I HDAC inhibitor and an siRNA of HDAC1 were used to treat HeLa cells. Autophagic markers were then investigated. Both inhibition and genetic knock-down of HDAC1 in the cells significantly induced autophagic vacuole formation and lysosome function. Moreover, disruption of HDAC1 leads to the conversion of LC3-I to LC3-II. Together, these results demonstrate that HDAC1 could play a role in autophagy and specific inhibition of HDAC1 can induce autophagy.     

Application of p21 and klf2 reporter gene assays to identify selective histone deacetylase inhibitors for cancer therapy

Novel 2-aminoanilide histone deacetylase (HDAC) inhibitors were designed to increase their contact with surface residues surrounding the HDAC active site compared to the contacts made by existing clinical 2-aminoanilides such as SNDX-275, MGCD0103, and Chidamide. Their HDAC selectivity was assessed using p21 and klf2 reporter gene assays in HeLa and A204 cells, respectively, which provide a cell-based readout for the inhibition of HDACs associated either with the p21 or klf2 promoter. A subset of the designed compounds selectively induced p21 over klf2 relative to the clinical reference compound SNDX-275. A representative lead compound from this subset had antiproliferative effects in cancer cells associated with induction of acetylated histone H4, endogenous p21, cell cycle arrest, and apoptosis. The p21- versus klf2-selective compounds described herein may provide a chemical starting point for developing clinically-differentiated HDAC inhibitors for cancer therapy.     

Sensitization of mesothelioma to TRAIL apoptosis by inhibition of histone deacetylase: role of Bcl-xL down-regulation

The TNF-related apoptosis-inducing ligand (TRAIL) is an immunological inducer of apoptosis selectively killing many, but not all, cancer cells. Malignant mesothelioma (MM) is fatal neoplasia with no current treatment, most likely due to high resistance of MM cells towards inducers of apoptosis, including TRAIL. We studied whether inhibition of histone deacetylase (HDAC), recently shown to sensitize malignant cells to a variety of apoptogenic substances, renders MM cells susceptible to TRAIL. Indeed, sub-apoptotic doses of the HDAC inhibitor suberohydroxamic acid (SBHA) sensitized MM cells to TRAIL apoptosis. Of the apoptotic mediators tested, the anti-apoptotic protein Bcl-x(L) was strongly down-regulated by combined treatment of the cells with SBHA and TRAIL but not by the HDAC inhibitor alone, while little or no change in the expression of other Bcl-2 family members highly expressed in MM cells, including Mcl-1 and Bax, was observed. Our data suggest a cross-talk between HDAC inhibition and TRAIL that results in modulation of expression of specific apoptotic mediators, and point to the potential of their combinatorial use in treatment of TRAIL-resistant neoplastic disease.     

A novel HDAC inhibitor with a hydroxy-pyrimidine scaffold

Histone deacetylases (HDACs) are enzymes involved in many important biological functions. They have been linked to a variety of cancers, psychiatric disorders, and other diseases. Since small molecules can serve as probes to study the relevant biological roles of HDACs, novel scaffolds are necessary to develop more efficient, selective drug candidates. Screening libraries of molecules may yield structurally diverse probes that bind these enzymes and modulate their functions in cells. Here we report a small molecule with a novel hydroxy-pyrimidine scaffold that inhibits multiple HDAC enzymes and modulates acetylation levels in cells. Analogs were synthesized in an effort to evaluate structure-activity relationships.     

Development of novel ferulic acid derivatives as potent histone deacetylase inhibitors

Histone deacetylase inhibitors (HDACIs) offer a promising strategy for cancer therapy. The discovery of potent ferulic acid-based HDACIs with hydroxamic acid or 2-aminobenzamide group as zinc binding group was reported. The halogeno-acetanilide was introduced as novel surface recognition moiety (SRM). The majority of title compounds displayed potent HDAC inhibitory activity. In particular, FA6 and FA16 exhibited significant enzymatic inhibitory activities, with IC₅₀ values of 3.94 and 2.82 μM, respectively. Furthermore, these compounds showed moderate antiproliferative activity against a panel of human cancer cells. FA17 displayed promising profile as an antitumor candidate. The results indicated that these ferulic acid derivatives could serve as promising lead compounds for further optimization.     

Search for novel histone deacetylase inhibitors. Part II: Design and synthesis of novel isoferulic acid derivatives

Previously, we described the discovery of potent ferulic acid-based histone deacetylase inhibitors (HDACIs) with halogeno-acetanilide as novel surface recognition moiety (SRM). In order to improve the affinity and activity of these HDACIs, twenty seven isoferulic acid derivatives were described herein. The majority of title compounds displayed potent HDAC inhibitory activity. In particular, IF5 and IF6 exhibited significant enzymatic inhibitory activities, with IC₅₀ values of 0.73 ± 0.08 and 0.57 ± 0.16 μM, respectively. Furthermore, these compounds showed moderate antiproliferative activity against human cancer cells. Especially, IF6 displayed promising profile as an antitumor candidate with IC₅₀ value of 3.91 ± 0.97 μM against HeLa cells. The results indicated that these isoferulic acid derivatives could serve as promising lead compounds for further optimization.