CN116327887B - 一种lsd1抑制剂作为抗肿瘤药物的应用 - Google Patents
一种lsd1抑制剂作为抗肿瘤药物的应用 Download PDFInfo
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Abstract
本发明公布了LSD1抑制剂及在抗肿瘤药物中的应用。本发明发现式I所示结构化合物具有显著的组蛋白赖氨酸特异性去甲基化酶LSD1抑制作用，为寻找基于组蛋白赖氨酸特异性去甲基化酶LSD1靶点的抗肿瘤药物开辟了一条新途径。
Description
技术领域
本发明属于抗肿瘤药物医药领域，目的在于提供一类组蛋白赖氨酸特异性去甲基化酶LSD1抑制剂在抗肿瘤药物中的应用。
背景技术
表观遗传与遗传错误协作通过改变基因活性而不改变DNA序列的方式促进癌症的发展和进展，DNA和与DNA相关的蛋白质修饰调控已经成为一个热门的研究领域，参与这些过程的酶也被认为是药物研发的热门靶点，组蛋白是其中之一。组蛋白尾部受到多种翻译后修饰的影响，例如：磷酸化、乙酰化、甲基化和泛素化，其中乙酰化和甲基化在基因表达的调节中起着重要的作用，并且在癌症中经常失调。
组蛋白赖氨酸特异性去甲基化酶LSD1可以特异性地去除组蛋白H3第4位赖氨酸(H3K4)和第9位赖氨酸(H3K9)的单、二甲基化，H3K4的甲基化通常与基因激活有关，H3K9的甲基化与转录抑制有关，相关过程与肿瘤的发生和发展密切相关。
组蛋白赖氨酸特异性去甲基化酶LSD1是一个高度保守的蛋白，存在于许多有机生命体中，具有三个主要结构域：利于蛋白质稳定的N-末端SWIRM结构域(小ɑ-螺旋结构域)、C末端的胺氧化酶结构域(AOL)和中心突出的TOWER结构域。TOWER结构域将AOL分为两个子结构域，即FAD结合区和底物结合区。组蛋白赖氨酸特异性去甲基化酶LSD1的活性中心，位于FAD和底物结合区域之间交叉点处的AOL结构域的中间。
组蛋白赖氨酸特异性去甲基化酶LSD1在多种肿瘤中过表达，包括横纹肌肉瘤、尤文肉瘤、骨肉瘤、***癌、乳腺癌、神经母瘤细胞、淋巴癌、肺癌、胃癌、结直肠癌、膀胱癌、食管癌或急、慢性白血病等，因此它是抗肿瘤药物的重要靶点。组蛋白赖氨酸特异性去甲基化酶LSD1的抑制可能是表观遗传沉默的肿瘤抑制基因重新表达的有效策略，能够抑制肿瘤的生长和转移。因此设计并研发选择性强、高效、低毒的组蛋白赖氨酸特异性去甲基化酶LSD1抑制剂是治疗癌症的新途径。
目前已经报道了几种组蛋白赖氨酸特异性去甲基化酶LSD1抑制剂，但它们的选择性差，对酶的抑制活性低，因此进一步研发高效，高选择性的组蛋白赖氨酸特异性去甲基化酶LSD1抑制剂仍然是一个有前景的目标。
发明内容
本发明目的在于提供一类组蛋白赖氨酸特异性去甲基化酶LSD1抑制剂在抗肿瘤药物中的应用，同时为LSD1抑制剂药物设计提供指导。
本发明上述目的通过以下技术方案实现：
本发明所述的式I所示的LSD1抑制剂：
本发明所述的式I所示的化合物已在ZINC20化合物库(https://zinc20.docking.org/)中报道，为现有已知化合物。
本发明提供式I所示的LSD1抑制剂或其药学上可接受的盐在制备组蛋白赖氨酸特异性去甲基化酶LSD1抑制剂药物中的应用。
本发明提供式I所示的LSD1抑制剂或其药学上可接受的盐在制备抑制肿瘤生长的药物中的应用。
本发明提供式I所示的LSD1抑制剂或其药学上可接受的盐在制备抑制肿瘤转移的药物中的应用。
本发明提供式I所示的LSD1抑制剂或其药学上可接受的盐在制备抑制肿瘤侵袭的药物中的应用。
本发明所述肿瘤包括横纹肌肉瘤、尤文肉瘤、骨肉瘤、***癌、乳腺癌、神经母瘤细胞、淋巴癌、肺癌、胃癌、结直肠癌、膀胱癌、食管癌或急、慢性白血病。
本发明所述药学上可接受的盐可以为这些化合物的常见盐，例如包括但不限于醋酸盐、硫酸盐、盐酸盐、草酸盐或磷酸盐。
本发明所述一类组蛋白赖氨酸特异性去甲基化酶LSD1抑制剂具有很好的抗横纹肌肉瘤等的作用。
附图说明
图1为式I化合物和LSD1蛋白的分子对接二维结果图。
图2为不同浓度的式I化合物对LSD1酶的抑制率曲线。
图3为式I化合物对A673细胞的增殖实验结果图。
具体实施方式
下面结合附图和具体实施方式来介绍本发明的实质性内容，但并不以此限定本发明的保护范围。
实施例1：分子对接验证
组蛋白赖氨酸特异性去甲基化酶LSD1蛋白使用PDB ID为2Z6U的晶体结构，解析度为把这个结构作为虚拟筛选中的受体，选取式I化合物化合物进行虚拟对接，检查式I化合物和组蛋白赖氨酸特异性去甲基化酶LSD1的对接姿势和相互作用。结果显示，式I化合物与组蛋白赖氨酸特异性去甲基化酶LSD1有关键的相互作用，见图1。
实施例2:动力学模拟分析验证
分子动力学模拟使用GROMACS进行。使用配体和组蛋白赖氨酸特异性去甲基化酶LSD1对接模型作为初始构象，配体的参数文件Ambertools准备，Amber99SB-ILDN力场用于受体蛋白，GAFF力场用于配体分子。溶剂采用TIP3P水模型。能量最小化后，复合体在NVT位置限制性中在250ps期间从0K加热到300K，在恒定1个大气压的压力即300K下平衡，再平衡50ps后进行动力学模拟。结果显示，醛基会与Ser289、Arg310和Arg318形成稳定的氢键相互作用。蛋白和小分子的短程库伦相互作用(Coul-SR:Protein-lig)和短程LJ势能见表1。
表1为式I化合物和LSD1复合物的动力学模拟结果。
| Energy | Average | RMSD | Tot-Drift |
| Potential | -4.581e+06 | 2306.67 | -182.268(kJ/mol) |
| Total Energy | -3.71418e+06 | 2928.58 | -180.884(kJ/mol) |
| Coul-SR：Protein-lig | -53.4071 | 26.4127 | 28.7022(kJ/mol) |
| LJ-SR：Protein-lig | -269.455 | 15.8264 | -14.1294(kJ/mol) |
实施例3：LSD1抑制活性测定
组蛋白赖氨酸特异性去甲基化酶LSD1可以特异性催化组蛋白H3K4或H3K9的去甲基化，同时产生H2O2。组蛋白赖氨酸特异性去甲基化酶LSD1的抑制实验是基于辣根过氧化物(horseradish peroxidase，HRP)检测原理，即在HRP存在下，H2O2与Amplex Red作用产生具有高度荧光的化合物试卤灵。将式I化合物配制为浓度在0-400nM之间的溶液，与人重组组蛋白赖氨酸特异性去甲基化酶LSD1酶在实验缓冲液(50mM磷酸钠pH7.4)和黄素腺嘌呤二核苷酸(FAD)于冰上孵育15min之后加入H3K4me2肽底物，37℃下孵育30min，加入Amplex Red试剂和辣根过氧化酶(HRP)，混合物在室温黑暗中孵育5min，使用酶标仪在激发光540nm，发射波长为570nm下分析荧光强度的变化得到数据，使用GraphPad软件经浓度-反应曲线拟合计算化合物的IC50值。结果显示，在体外式I化合物对组蛋白赖氨酸特异性去甲基化酶LSD1酶有明显的抑制作用，见图2。
实施例4：细胞增殖实验
培养A673细胞至对数生长期，用胰蛋白酶对细胞进行消化，终止消化后离心，制备成单细胞悬液，密度为5000个/孔接种于96孔细胞培养板中，培养箱中培养过夜弃去培养基，对照组加入培养基，LSD1抑制剂组分别加入含有浓度为100μg/ml、50μg/ml、25μg/ml、12.5μg/ml的式I化合物的培养基，培养箱中培养72h，加入10μl的MTT溶液，继续培养4h后，弃去MTT溶液每孔加入150μl的DMSO，室温在摇床上放置15min，利用酶标仪检测570nm处的光密度。使用GraphPad软件经浓度-反应曲线拟合计算化合物的抑制率。结果显示，式I化合物对A673细胞有明显的抑制作用，且结果具有统计学差异，见图3。
Claims (2)
1.式I所示的LSD1抑制剂或其药学上可接受的盐在制备组蛋白赖氨酸特异性去甲基化酶LSD1抑制剂药物中的应用
式 I。
2.根据权利要求1所述的应用，其特征在于，所述药学上可接受的盐为醋酸硫盐、盐酸盐、草酸盐或磷酸盐。
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