CN103893163A - 2-([1,1’-联苯]-4-基)-2-氧代乙基 4-((3-氯-4-甲基苯基)氨基)-4-氧代丁酸酯在制备lsd1抑制剂药物中的应用 - Google Patents
2-([1,1’-联苯]-4-基)-2-氧代乙基 4-((3-氯-4-甲基苯基)氨基)-4-氧代丁酸酯在制备lsd1抑制剂药物中的应用 Download PDFInfo
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Abstract
本发明属于药学领域，具体涉及式I所示的2-([1，1′-联苯]-4-基)-2-氧代乙基4-((3-氯-4-甲基苯基)氨基)-4-氧代丁酸酯作为选择性的组蛋白赖氨酸特异性去甲基化酶1(LSD1)抑制剂的医药用途，特别是在抗肿瘤药物中的应用。药效学试验表明其具有显著的LSD1抑制作用，并且对同源蛋白MAO-A和MAO-B有选择性。
Description
技术领域
本发明属于药学领域，具体涉及2-([1，1′-联苯]-4-基)-2-氧代乙基4-((3-氯-4-甲基苯基)氨基)-4-氧代丁酸酯作为选择性作用的组蛋白赖氨酸特异性去甲基化酶1(LSD1)抑制剂的医药用途。本发明还涉及2-([1，1′-联苯]-4-基)-2-氧代乙基4-((3-氯-4-甲基苯基)氨基)-4-氧代丁酸酯的药物制剂或药物组合物的医药用途，特别是制备抗肿瘤药物中的应用。
背景技术
2004年，哈佛医学院施扬课题组发现了第一个组蛋白赖氨酸特异性去甲基化酶1(Lysine Specific Demethylase1，LSD1)，首次确认组蛋白甲基化是一个动态平衡过程(Cell，2004，119：941-953)，这一革命性发现对组蛋白修饰的作用机制及其相应的药物研究提供了全新的研究思路。LSD1是一种黄素腺嘌呤二核苷酸(flavin adenine dinucleotide，FAD)依赖的去甲基化酶，能够去除H3K4和H3K9的单、双甲基，从而调节组蛋白和其他蛋白的相互作用，并影响基因转录的激活、抑制和染色体失活等过程。
LSD1属于胺氧化酶家族成员，晶体结构显示LSD1主要由三部分组成：N端的SWIRM(Swi3p／Rsc8p／Moira)结构域，C端的胺基氧化酶(Amine oxidase like，AOL)结构域(分为FAD结合结构域和底物结合结构域，两者组成催化活性中心)和中心定位一个Tower结构域(PNAS，2006,103(38)：13956-13961)。LSD1是胺基氧化酶的同源蛋白，与多胺氧化酶(Polyamine Oxidase，PAO)的相似度为22.4％，与单胺氧化酶A和B(Monoamine Oxidase A and B，MAO-A and MAO-B)的相似度为17.6％。
LSD1主要通过以下3个途径来调节基因的表达：(1)通过CoREST的SANT2结构域与靶基因结合，引起H3K4去甲基化，从而导致转录抑制；(2)LSD1与雄激素／雌激素受体结合后，能使H3K9去甲基化，引起激素受体依赖的基因转录激活；(3)LSD1通过对H3K4的去甲基化，使得DNA甲基转移酶(DNMTs)的正调控因子DNMT3L能够与未甲基化的K4位点结合，促进DNMTs的表达，引起DNA重新甲基化(Denovo methylation)，从而导致基因转录抑制(Nature，2007，448(7154)：714-717；Nat Genet,2009，41(1)：125-129)。
研究发现，LSD1在多种肿瘤中高表达，如神经母瘤细胞、前列腺癌、乳腺癌、肺癌、膀胱癌等。例如，Huang等应用LSD1的多胺类似物抑制剂bisguanidine1c抑制人结肠癌细胞的LSD1活性，引起一些异常沉默的基因(SFRP1、SFRP4、SFRP5和GATA5)重新表达，从而诱发 细胞凋亡(PNAS，2007，104(19)：8023-8028)。Schulte等报道LSD1与神经母细胞瘤分化密切相关，该研究组发现低分化的神经母细胞瘤中LSD1高表达，siRNA敲除LSD1后，瘤细胞的生长受抑制，体内实验证实LSD1可以抑制神经母细胞瘤的生长(CancerRes，2009，69(5)：2065-2071)。
目前，已报道的LSD1抑制剂主要有多肽类、苯环丙胺类、多胺类和其他类小分子LSD1抑制剂(Expert Opin.Ther.Targets，2012，16(12)：1239-1249)。研究最多的是苯环丙胺类LSD1抑制剂，其分子结构中的苯环丙胺与FAD共价结合，从而抑制LSD1的生物学功能，其结合作用具有不可逆性，并且苯环丙胺类LSD1抑制剂对MAOs选择性较差，因而毒副作用较大。此外，已报道的LSD1抑制剂对同源蛋白MAOs的选择性也普遍不高。因此，发现选择性强、高效低毒的LSD1抑制剂是癌症治疗的新途径之一。
发明内容
本发明公开了式I化合物作为一类全新骨架的选择性作用的组蛋白赖氨酸特异性去甲基化酶1(LSD1)抑制剂的医药用途。
本发明的一个目的是提供了式I化合物在制备LSD1抑制剂的应用。
式I化合物购自荷兰Specs公司(http：／／www.specs.net)，编号：AK-918／11939057，中文名：2-([1，1′-联苯]-4-基)-2-氧代乙基4-((3-氯-4-甲基苯基)氨基)-4-氧代丁酸酯，CAS号：332024-26-7。
式I化合物具有强效的体外LSD1抑制作用(ICs0=2.41μM，对照品Tranylcypromine，IC50=4.64μM)，并对同源蛋白MAO-A／B具有选择性，其IC50值分别为685μM和27.5μM，选择性(IC50：MAO-A／LSD1，MAO-B／LSD1)分别为284.2和11.4。
本发明的又一个目的是提供了式I化合物在制备抗肿瘤药物中的应用。
本发明的再一个目的是提供了含有式I化合物的药物制剂或药物组合物。
本发明包括含有式I化合物的药物制剂，其特征在于，其剂型为固体口服剂、液体口服剂或注射剂，所述的固体口服剂可以是片剂、丸剂、分散片、咀嚼片、口崩片、胶囊或颗粒 剂；所述的液体口服制剂可以是口服溶液剂；所述的注射剂可以是注射用水针、注射用冻干粉针、大输液或小输液。
本发明包括一种药物组合物，其中含有治疗有效量的式I化合物。
本发明还一个目的是提供了式I化合物、药物制剂及药物组合物，用于制备治疗由LSD1介导的疾病的药物中的应用。疾病，包括肿瘤、病毒感染和神经退行性疾病。肿瘤，包括白血病、前列腺癌、乳腺癌、肺癌、肝癌、皮肤癌、结直肠癌、淋巴癌、血癌或骨瘤癌。白血病，包括急性髓性白血病、慢性髓性白血病、慢性中性粒细胞性白血病、慢性嗜酸细胞性白血病、慢性淋巴细胞性白血病、急性淋巴母细胞性白血病或多毛细胞白血病。
与现有的LSD1抑制剂相比，本发明的式I化合物具有下述优势：(1)全新骨架，不同于现有的LSD1抑制剂，特别是不同于苯环丙胺类LSD1抑制剂；(2)良好的LSD1抑制活性，强于苯环丙胺类LSD1抑制剂Tranylcypromine；(3)对同源蛋白MAO-A／B具有选择性。因此，可作为选择性LSD1抑制剂用于制备抗肿瘤药物。
附图说明
图1表示式I化合物抑制LSD1的量效曲线。
图2表示式I化合物抑制MAO-A的量效曲线。
图3表示式I化合物抑制MAO-B的量效曲线。
具体实施方式
提供下列实施例为了进一步举例说明本发明，而不是对本发明范围的限定。
实施例1式I化合物的LSD1体外筛选
1.试剂与原料
LSD1：(Enzo cat#BML-SE544，N端截短的LSD1来源于大肠杆菌中表达的人源cDNA，序列与基因库NM015013(氨基酸151-852)相同，相对分子量：78kDa)
反应底物：10μM的二甲基化H3K4的21肽(Histone H3peptide(1-21)K4me2，10μM)
碱性反应缓冲液：50mM的Tris-HCl，pH值为7.5和1％DMSO
反应条件：100nM的LSD1和10μM的二甲基化H3K4的21肽
2.操作步骤
2.1去甲基化步骤
(1)每个反应孔中加入2倍量LSD1
(2)应用Acoustic技术(Echo550；纳升范围)将待测样品用100％的DMSO溶解后加入 酶中，降速并预孵育15分钟。
(3)加入2倍量底物混合物(除了没有底物的对照孔)以引发反应。在无底物的反应孔中加入缓冲液。旋转并摇晃。
(4)室温孵育1小时。
2.2检测步骤
(1)预先混合辣根过氧化物酶HRP与荧光染料Amplex Red，并将此检测用混合物加入到反应中。
(2)酶标仪Envision测量30分钟，时间间隔5分钟(激发光535nm，发射光590nm)。
(3)当信号到达平台后，收取端点数据用于分析。
3数据分析
由去掉背景的测试信号值(以无底物时测得信号为背景)计算相对于DMSO空白的活性(％)，用GraphPad Prism4计算(sigmoidal dose-response(variable slope)；4parameters with Hill Slope.)。设定限制条件：底部=0，顶部<120。
4实验结果见MAO-A和MAO-B筛选部分。
实施例2式I化合物对MAO-A和MAO-B的体外筛选
1.试剂与原料
MAO-A：Sigma cat#M7316(人源重组，表达在杆状病毒感染的BTI的昆虫细胞，84U／mg).
MAO-B：Sigma cat#M7441(人源重组，表达在杆状病毒感染的BTI的昆虫细胞，71U／mg.)
底物：10μM的酪胺Tyramine
碱性反应缓冲液：50mM的Tris-HCl，pH值为7.5和1％DMSO
反应条件：MAO-A(0.5U／ml)、MAO-B(1U／ml)和酪胺(10μM)
2.操作步骤
2.1去甲基化步骤
(1)每个反应孔中加入2倍量LSD1
(2)应用Acoustic技术(Echo550；纳升范围)将待测样品用100％的DMSO溶解后加入酶中，降速并预孵育15分钟。
(3)加入2倍量底物混合物(除了没有底物的对照孔)以引发反应。在无底物的反应孔中加入缓冲液。旋转并摇晃。
(4)室温孵育1小时。
2.2检测步骤
(1)预先混合辣根过氧化物酶HRP与荧光染料Amplex Red，并将此检测用混合物加入到反应中。
(2)酶标仪Envision测量30分钟，时间间隔5分钟(激发光535nm，发射光590nm)。
(3)当信号到达平台后，收取端点数据用于分析。
3数据分析
由去掉背景的测试信号值(以无底物时测得信号为背景)计算相对于DMSO空白的活性(％)，用GraphPad Prism4计算(sigmoidal dose-response(variable slope)；4parameters with Hill Slope.)。设定限制条件：底部=0，顶端<120。
4实验结果
式I化合物抑制LSD1、MAO-A和MAO-B的量效曲线分别如附图1、2和3所示。
实验结果表明：本发明的式I化合物具有显著的LSD1抑制活性，强于苯环丙胺类LSD1抑制剂Tranylcypromine，并且对同源蛋白MAO-A／B特别是MAO-A具有出人意料地选择性，可以用于制备LSD1抑制剂药物。
实施例3式I化合物的片剂制备
采用湿法制粒压片法，将式I化合物与各种辅料如羟丙甲基纤维素E5、微晶纤维素MCC102、8％聚维酮K30和硬脂酸镁按如下比例混合、粉碎过筛、制粒、干燥、压片制作相应的片剂。
Claims (9)
1.式I化合物在制备组蛋白赖氨酸特异性去甲基化酶1抑制剂中的应用。
2.权利要求1所示的式I化合物在制备治疗肿瘤药物中的应用。
3.一种药物制剂，其特征在于，含有式I化合物，以及药学上可接受的添加剂或／和载体。
4.权利要求3所述的药物制剂，其特征在于，其剂型为固体口服剂、液体口服剂或注射剂，所述的固体口服剂可以是片剂、丸剂、分散片、咀嚼片、口崩片、胶囊或颗粒剂；所述的液体口服制剂可以是口服溶液剂；所述的注射剂可以是注射用水针、注射用冻干粉针、大输液或小输液。
5.一种药物组合物，其特征在于，含有治疗有效量的式I化合物。
6.权利要求1至5中任意一项权利要求中所述的式I化合物、药物制剂或药物组合物，用于制备由组蛋白赖氨酸特异性去甲基化酶1介导的疾病的药物中的应用。
7.权利要求6所述的疾病，包括肿瘤、病毒感染和神经退行性疾病。
8.权利要求7所述的肿瘤，其特征在于白血病、前列腺癌、乳腺癌、肺癌、肝癌、皮肤癌、结直肠癌、淋巴癌、血癌或骨瘤癌。
9.权利要求8所述的白血病，包括急性髓性白血病、慢性髓性白血病、慢性中性粒细胞性白血病、慢性嗜酸细胞性白血病、慢性淋巴细胞性白血病、急性淋巴母细胞性白血病或多毛细胞白血病。
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