组蛋白去乙酰化酶抑制剂抗肿瘤临床研究进展

综述了近年来组蛋白去乙酰化酶(HDAC)抑制剂作为抗肿瘤药的临床研究进展。组蛋白去乙酰化酶抑制剂可以引导肿瘤细胞生长停滞、分化和凋亡,是很有前途的癌症治疗药物。目前,超过十多种组蛋白去乙酰化酶抑制剂作为治疗血液肿瘤和恶性实体瘤药物,有上百个临床试验正在进行中。     

组蛋白去乙酰化酶抑制剂的研究进展

表观遗传学是目前遗传学研究的热点,而肿瘤的发生与表观遗传学关系密切.表观遗传修饰中组蛋白乙酰化酶(HAT)和组蛋白去乙酰化酶(HDAC)之间的动态平衡控制着染色质结构和基因表达.HDAC抑制剂作为新一代潜在靶向抗肿瘤药物,为国内外药学研究的热点.本文综述HDAC抑制剂的作用机制及临床研究进展.     

组蛋白去乙酰化酶抑制剂抗肿瘤作用研究进展

组蛋白去乙酰化酶(histone deacetylase, HDAC)在肿瘤发生和发展的多个环节中扮演着非常重要的角色,如肿瘤抑癌基因沉默、细胞分化、血管生成、细胞迁移、细胞周期异常、信号传导及细胞附着等。组蛋白去乙酰化酶抑制剂(histone deacetylase inhibitors, HDACIs)可以靶向组蛋白去乙酰化酶调控组蛋白的乙酰化,进而调控关键的抑制肿瘤蛋白和原癌基因,是极具潜力的抗肿瘤药物。HDACIs已经在血液/淋巴系统肿瘤治疗方面取得了一定成果,目前已经有2种HDACIs：SAHA(suberoylanilide hydroxamic acid)和FK228被批准用于治疗皮肤T细胞淋巴癌,当前大量的临床试验正在挖掘HDACIs在实体瘤治疗方面的潜力。尽管目前基于细胞的研究发现HDACIs可以诱导肿瘤细胞凋亡,细胞周期抑制,细胞分化,抑制血管生成和自噬等,但HDACIs发挥抗肿瘤活性的分子机制仍未阐明,其对实体瘤的临床治疗效果及相关治疗策略有待进一步确证。     

组蛋白去乙酰化酶抑制剂的研究进展

组蛋白去乙酰化酶（HDACs）是一类对染色体的结构修饰和基因表达调控发挥着重要作用的蛋白酶,与肿瘤的发生发展关系密切。组蛋白去乙酰化酶抑制剂（HDACIs）在抗肿瘤药物的开发中具有重要意义。本文对HDACs分子结构、HDACs与肿瘤的关系、HDACIs化学结构及其目前主要的设计思路、构效关系进行综述。     

在治疗肿瘤领域中组蛋白去乙酰化酶抑制剂的研究进展

近年来在治疗肿瘤领域中组蛋白去乙酰化酶（HDAC）抑制剂的研究已成为热点。组蛋白乙酰化转移酶（HAT）与组蛋白去乙酰化酶（HDAC）之间保持的动态平衡调控着有序的基因表达, HDAC表达过度造成乙酰化的失衡会形成肿瘤,而HDAC抑制剂可诱导肿瘤细胞分化、细胞周期停滞和凋亡,抑制肿瘤的生成。HDAC抑制剂是很有前途的新型癌症靶向治疗药物。本文将重点阐述HDAC抑制剂的作用机制以及在肿瘤治疗领域中的研究进展。     

组蛋白去乙酰化酶抑制剂恩替诺特

组蛋白去乙酰化酶(HDAC)是一类对染色质结构修饰和基因表达调控起重要作用的蛋白酶。因HDAC具有转录抑制功能,被视为是一类新兴的癌症药物靶点。HDAC过度表达影响包括乳腺癌在内的一些癌症的进程。抑制HDAC的表达或活性能够为治疗癌症提供新策略。恩替诺特是一种口服合成的苯甲酰胺衍生物类HDAC抑制剂,很有潜力成为抗癌药物,特别是乳腺癌治疗药物。多项临床试验研究表明恩替诺特具有安全性和有效性。     

组蛋白去乙酰化酶抑制剂抗肿瘤机制研究进展

肿瘤是威胁人类身体健康严重疾病之一,传统抗肿瘤药物因为选择性差而容易引起比较严重的毒副作用。随着近些年来临床医学研究水平的不断提高,有关肿瘤致病与发病机制的相关基本过程也逐渐被阐明,新型的抗肿瘤药物组蛋白去乙酰化酶（HDAC）抑制剂在临床中广泛应用开来。HDAC抑制剂能够作用于患者的肿瘤细胞,使肿瘤细胞的增殖受抑制,诱导肿瘤细胞凋亡,具有非常高的临床应用价值。本文就HDAC抑制剂在抗肿瘤方面所取得的效果以及药用机制等问题做了相关描述,供相关人员做参考。     

食管鳞癌组织中组蛋白去乙酰化酶2的表达及临床意义

目的探讨组蛋白去乙酰化酶2(HDAC2)在食管鳞癌组织中的表达及其临床意义。方法应用实时荧光定量PCR及Western blot法检测30例配对人食管鳞癌(A组)和癌旁组织(C组)中HDAC2蛋白及其mRNA的表达。免疫组化方法检测90例(B组)食管鳞癌组织中HDAC2的表达水平,分析其与临床和病理特性的相关性。结果 A组HDAC2蛋白及其mRNA表达量均显著高于C组(P<0.01)。免疫组化结果显示,B组HDAC2蛋白表达阳性率为79%(71/90),HDAC2表达强度与TNM分期和淋巴结转移相关(P<0.05),而与患者年龄、性别、肿瘤大小、肿瘤位置、病理学大体分型、浸润深度及分化程度无关(P>0.05)。结论 HDAC2高表达可能是食管鳞癌的特征之一,在一定程度上可以反映肿瘤的恶性程度,可作为判断食管鳞癌患者预后的指标。     

组蛋白去乙酰化酶抑制剂的合成及其体外抗肿瘤研究

目的设计并合成组蛋白去乙酰化酶抑制剂(HDACi),并对其组蛋白去乙酰化酶(HDACs)抑制活性和体外抗肿瘤活性进行研究。方法以N-Boc-对苯二胺和辛二酸酐为起始原料,反应制得7-(N-Boc-氨基)苯胺甲酰基庚酸,再通过胺醛缩合反应合成HDACi;并采用HDACs试剂盒和CCK-8试剂盒测试所合成目标化合物抑制HDACs的活性和抗肿瘤活性。结果合成了26个新化合物,其结构均经过核磁共振氢谱和质谱进行了确证。初步的生物活性测试结果表明,所合成的目标化合物对HDACs的抑制活性均强于阳性药物伏立诺他,并对MCF-7、PC-3、HepG2、MGC-803和KB 5种肿瘤细胞有不同程度的抑制活性,其中希夫碱含有吸电子基的化合物对HDACs的抑制活性以及抗肿瘤活性强于其他衍生物。尤其是4-氰基化合物11c对HDACs展现出了最强的抑制活性,是阳性药伏立诺他的58倍;同时,化合物11c对肿瘤细胞MCF-7、PC3、MGC-803和HepG2展现出了最强的抗肿瘤活性,其抗胃癌MGC-803甚至是阳性药物伏立诺他的7.2倍。结论希夫碱是一类重要的抗肿瘤药效团,能够提高HDACi的抗肿瘤活性,为今后发展新型、高效的HDACi提供了新的思路。     

组蛋白去乙酰化酶抑制剂的抗肿瘤活性

组蛋白去乙酰化酶（HDAC）与染色质重塑有关，在基因表达的表观遗传调控中扮演重要角色。此外，HDAC介导的低乙酰化作用可调节非组蛋白活性。近年来，抑制组蛋白去乙酰化酶成为逆转与肿瘤相关的表观遗传异常改变的潜在策略。临床前研究发现，多种组蛋白去乙酰化酶抑制剂（HDACi）表现出有效的、特异的抗肿瘤活性，然而其疗效相当广泛和复杂。     

The clinical development of histone deacetylase inhibitors as targeted anticancer drugs

Importance of the field: Histone deacetylase (HDAC) inhibitors are being developed as a new, targeted class of anticancer drugs.

Area covered in this review: This review focuses on the mechanisms of action of the HDAC inhibitors, which selectively induce cancer cell death.

What the reader will gain: There are 11 zinc-dependent HDACs in humans and the biological roles of these lysine deacetylases are not completely understood. It is clear that these different HDACs are not redundant in their activity. This review focuses on the mechanisms by which HDAC inhibitors can induce transformed cell growth arrest and cell death, inhibit cell mobility and have antiangiogenesis activity. There are more than a dozen HDAC inhibitors, including hydroxamates, cyclic peptides, benzamides and fatty acids, in various stages of clinical trials and many more compounds in preclinical development. The chemically different HDAC inhibitors may target different HDACs.

Take home message: There are extensive preclinical studies with transformed cells in culture and tumor-bearing animal models, as well as limited clinical studies reported to date, which indicate that HDAC inhibitors will be most useful when used in combination with cytotoxic or other targeted anticancer agents.     

Histone deacetylase inhibitors: from target to clinical trials

Transformed cells, characterised by inappropriate cell proliferation, do not necessarily lose the capacity to undergo growth arrest under certain stimuli. DNA, genetic information, is packaged in chromatin proteins, for example, histones. The structure of chromatin may be altered by post-translational modifications (e.g., acetylation, phosphorylation, methylation and ubiquitylation) which play a role in regulating gene expression. Two groups of enzymes, histone deacetylases (HDACs) and acetyl transferases, determine the acetylation status of histones. This review focuses on compounds that inhibit HDAC activity. These agents have been shown to be active in vitro and in vivo in causing cancer cell growth arrest, differentiation and/or apoptosis. Several HDAC inhibitors are currently in clinical trials as anticancer agents and, in particular, hydroxamic acid-based HDAC inhibitors have shown activity against cancers at well-tolerated doses.     

Histone deacetylase inhibitors

Sustained efforts towards identifying novel histone deacetylase (HDAC) inhibitors as suitable therapies for the treatment of cancer and other human diseases has been a goal for the pharmaceutical industry during the last decade. In the second half of 2006 these efforts culminated in the FDA granting approval for the first HDAC inhibitor, suberoylanilide hydroxamic acid; also known as vorinostat, for once-daily oral treatment of advanced cutaneous T cell lymphoma. This review provides a summary of the published patent literature from mid-2005 until the end of 2006.     

Design,synthesis, and biological characterization of tamibarotene analogs as anticancer agents

In our efforts of developing novel compounds as potential anticancer agents, a series of tamibarotene analogs containing Zn²⁺‐binding moieties were designed and developed. Biological characterization identified compound 7b as the most potent one with improved antiproliferative activities against multiple cancer cell lines, compared to parent compound tamibarotene. Further characterization also demonstrated that compound 7b exhibited moderate activities as a histone deacetylase inhibitor with IC₅₀ of 1.8 ± 0.1 μm , thus suggesting that this could contribute to the improved antiproliferative activities of 7b . Pharmacokinetic studies revealed that compound 7b could release tamibarotene after administration and prolong the circulation time of tamibarotene, and this may also potentially contribute to the improved antiproliferative activities. Collectively, the results demonstrated that compound 7b could serve as a new lead for further development of more potent analogs as potential anticancer agents.     

N-芳乙基异喹啉衍生物的合成及其抗肿瘤活性研究

本研究采用一种简便的新方法设计合成了一系列全新结构的N-芳乙基异喹啉衍生物, 并对其体外抗肿瘤活性进行了评价。其中化合物9a表现出较强的抗肿瘤活性, 对人肝癌HepG2和大肠癌HCT116细胞的IC₅₀值分别为2.52和1.99 μg·mL^–1。初步作用机制显示, 9a可以将HepG2细胞周期阻滞于S期, 使细胞增殖受阻, 达到抗肿瘤效果。     

Novel histone deacetylase 6 (HDAC6) selective inhibitors: a patent evaluation (WO2014181137)

Introduction: Histone deacetylases (HDACs) are known to deacetylate histones and other proteins, which makes HDAC inhibitors able to affect cell survival, cell signaling, transport, and gene expression. Those effects have been associated to the therapeutic success of HDAC inhibitors. Class I-selective or pan-HDAC inhibitors have been approved for cancer therapy by the US Food and Drug Administration (FDA). Moreover, HDAC6 selective inhibitors entered phase I and II clinical trials for treating multiple myeloma. The development of potent and selective HDAC inhibitors is a hot topic in current drug discovery.

Areas covered: The invention described in this patent (WO2014181137) is related to hydroxamic acid derivatives with inhibitory activity towards HDACs, their synthetic process and pharmaceutical formulations, as well as a method for treating patients suffering from a list of selected tumoral, inflammatory, cardiac and chronic disorders.

Expert opinion: The compounds disclosed within this patent are selective against HDAC6 and their structure is related to tubastatin A, a known HDAC6 selective inhibitor. They are newly synthesized diarylamines showing an improved selectivity profile compared to other diarylamines under clinical investigation.     

PKD1/HDAC5轴在心肌梗死大鼠损伤心肌组织修复中的作用

摘要：目的 分析蛋白激酶D1（PKD1）/Ⅱa类组蛋白去乙酰化酶5（HDAC5）轴对受损心肌梗死大鼠心肌修复的 影响。方法 根据随机数字表法把40只Wistar大鼠划分为4组：假手术组、模型组、PKD1（2 mg·kg-1·d-1 PKD1）用药组和阻断剂CID755673（2 mg·kg-1·d-1 PKD1+10 ng·kg-1·d-1 CID755673）组,每组10只。模型组采用经典的左冠状动脉结扎术复制心肌梗死模型,假手术组开胸手术但没有进行结扎处理。模型组和假手术对照组均给予治疗组相同剂量的生理盐水。采用间隔1日1次的尾静脉注射方式给药,共28 d。采用HE染色分析心肌组织病理变化,Masson染色分析心肌组织的胶原变化,TUNEL法检测心肌细胞的凋亡程度,免疫印迹法和免疫组化染色检测心肌细胞HDAC5、肌细胞增强因子2（MEF2）和心肌肌钙蛋白I（cTn I）的表达。结果 心肌组织病理变化表明,假手术组大鼠心肌组织正常,无坏死和炎症浸润,胶原占比很低,偶见凋亡的心肌细胞,HDAC5和MEF2阳性细胞数量较少,cTn I阳性细胞数量较多;和假手术组相比,模型组大鼠心肌组织坏死明显,伴炎症浸润,胶原占比、凋亡的心肌细胞数量和MEF2阳性细胞数量均显著增加（P＜0.05）,cTn I阳性细胞数量显著减少（P＜0.05）。和模型组相比,PKD1治疗能显著改善心肌梗死大鼠心肌坏死程度,使受损心肌组织胶原占比、凋亡的心肌细胞数量和MEF2阳性细胞数量均显著减少（P＜0.05）,cTn I阳性细胞数量显著升高（P＜0.05）;而CID755673可以阻断PKD1的这一治疗作用。结论 PKD1可能具有结合HDAC5促心肌梗死大鼠损伤心肌组织修复的作用,这一作用能够被CID755673所阻断。     

组蛋白去乙酰酶抑制剂的药理学研究进展

组蛋白的乙酰化调节,参与了基因表达的调控;组蛋白乙酰转移酶和组蛋白去乙酰酶活性共同决定了组蛋白的乙酰化水平.组蛋白去乙酰酶抑制剂可提高组蛋白的乙酰化水平,并对一些非组蛋白成分产生影响,从而调节某些特定基因的表达.综述了组蛋白去乙酰酶抑制剂的药理作用及其临床应用前景.     

Patent status of histone deacetylase inhibitors

Histone deacetylase (HDAC) has emerged as an important therapeutic target for the treatment of cancer and other diseases. Several HDAC inhibitors that target class I and II HDACs are currently in clinical trials. The initial results from these studies indicate that HDAC inhibitors show great promise for the treatment of cancer. To date, more than 30 research organisations are named as applicants on published patent applications claiming structures of HDAC inhibitors. This review summarises the patent literature published from mid-2002 to early 2004 containing claims directed towards HDAC inhibitor structures, together with discussion of the related primary literature.