CN112250637A - 虚拟筛选的化合物在制备抗肿瘤药物中的应用及其药物 - Google Patents
虚拟筛选的化合物在制备抗肿瘤药物中的应用及其药物 Download PDFInfo
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Abstract
本发明通过采用分子对接软件MOE2019对含90多万小分子分子化合物的CHEMDIV数据库进行搜寻，分别采用药效团模拟、类药五规则以及分子对接进行逐级筛选，获得了含有通式(Ⅰ)所示结构的化合物。该化合物具有抑制CDK8激酶的作用，是发明人新发现的CDK8激酶抑制剂，且该化合物通过抑制CDK8激酶进一步抑制肿瘤细胞的生长，从而达到抑制肿瘤的作用。
Description
技术领域
本发明涉及药物领域，具体涉及一种虚拟筛选的小分子化合物在制备抗肿瘤药物中的应用，以及以该化合物作为活性组分用于治疗肿瘤的药物。
背景技术
肿瘤是一种细胞周期性疾病，而CDK8是调节细胞周期的关键激酶之一，针对肿瘤细胞的异常增殖，可以通过抑制CDK8蛋白酶的功能，从而达到抗癌的效果。
肿瘤的发生常常伴有失控的细胞增殖，是一种细胞周期性疾病。细胞周期的异常进行会影响细胞的增殖、凋亡等活动，从而诱发肿瘤的产生。因此，研发针对细胞周期的药物成为了抗肿瘤药物的一个研发热点。通过使细胞周期停止来抑制肿瘤细胞增殖，从而达到抑制肿瘤发展的效果。并且在研究中已经证明了，抑制肿瘤细胞持续的细胞周期是有效的。
目前发现的调控细胞周期的分子主要有三类：细胞周期蛋白(cyclin)、细胞周期蛋白依赖性激酶(CDKs)和细胞周期蛋白依赖性激酶抑制物，这三类分子通过相互作用来进行复杂的细胞周期调控。肿瘤的细胞周期缺陷通常是由CDKs活性的改变导致的。细胞周期蛋白依赖性激酶(cyclin dependent kinase，CDKs)，属于丝氨酸/苏氨酸蛋白激酶家族，是调节细胞周期的关键激酶。目前已经报道的约有20个不同的CDKs，其同源序列PSTAIRE与相应的调节亚基——细胞周期蛋白结合之后将会活化，继而参与转录、代谢和发育等生理过程。CDKs可以促进细胞周期相转变、启动DNA合成及调控转录等，在细胞的增殖、分化中起着重要的作用。有研究表明，CDKs异常表达，会扰乱细胞的增殖、分化和凋亡，进而导致恶性肿瘤的发生，在多种肿瘤中都观察到了CDKs相关通路的改变。
CDK8与CDK家族的其他成员不同，不直接调节细胞周期进程。其作为多效的转录调节因子，可增强多种转录因子对转录的诱导，介导了多种致癌信号通路，因而受到了广泛的关注。细胞周期蛋白依赖性激酶8(CDK8)是含有464个氨基酸的53kD的蛋白激酶，和细胞周期蛋白C(Cyc C)结合后变为活性状态，调节RNA Pol II介导的转录，从而调控基因的转录过程。最初在结肠癌(CRC)的研究中发现CDK8介导了β-连环蛋白的异常活化，加速细胞周期的进行。随后，在多种肿瘤中均发现了它的过表达，如胃癌、乳腺癌、黑色素瘤等，并且在去除CDK8之后均显示出了一定的抗肿瘤活性。大量证据表明CDK8在多种癌症中具有致癌蛋白的作用，并证实抑制CDK8可抑制肿瘤生长，增强NK细胞的细胞毒性。这激发了人们对开发CDK8抑制剂作为潜在抗癌药物的兴趣。因此，抑制肿瘤细胞中CDKs的过度表达，从而阻滞细胞周期并最终诱导肿瘤细胞凋亡，成为了一种极具前景的肿瘤治疗策略。
基于CDK8在肿瘤细胞中的调节作用，CDK8可以被看作一个新的肿瘤标记物，可通过开发新的CDK8激酶抑制剂来治疗癌症。然而，直到近几年其晶体结构被确定之后，才开始发现大量的特异性抑制剂，但是只有少数的CDK8抑制剂达到了临床试验，还没有批准上市的药物。提高其选择性和探究其作用机制是CDK8抑制剂开发的重大挑战，因此开发新的具有良好的药理作用的CDK8抑制剂具有重要的意义。
发明内容
本发明的目的在于提供虚拟筛选的化合物在制备抗肿瘤药物中的应用及其药物。发明人采用分子对接软件MOE2019对含90多万小分子分子化合物的CHEMDIV数据库进行搜寻，分别采用药效团模拟、类药五规则以及分子对接进行逐级筛选，期望发现具有全新结构的CDK8激酶抑制剂化合物，为开发抗肿瘤领域提供新的药物。
本发明在充分调研已有CDK8激酶抑制剂的结构特征以及晶体复合物结合位点的基础上，辅之以合理的筛选方式，开展了大规模虚拟筛选新结构类型CDK8激酶抑制剂的研究工作，最后成功发现了一系列新的CDK8激酶抑制剂。
本发明通过虚拟筛选获得具有通式(Ⅰ)结构的CDK8激酶抑制剂，所述抑制剂具有抗肿瘤的功能，其具体通式如下：
式(Ⅰ)：
其中：
R1为氢，或为1-4个碳原子的烷氧基，或为1-4个碳原子的烷基；
R2为氢，或为
或为
或为
以上通式所含化合物均可购得或由本领域普通技术人员采用已知合成路线无需创造性劳动即可得到，它们的抗肿瘤用途未被现有技术公开。该类通式所含的母核结构，是保证该类化合物作为CDK8激酶抑制剂以及具有抗肿瘤活性的关键。
优选地，所述化合的结构如式(Ⅱ)所示：
优选地，所述化合的结构如式(Ⅲ)所示：
优选地，所述化合的结构如式(Ⅳ)所示：
发明人通过实施例实验验证了本发明化合物对CDK8激酶的抑制活性以及对肿瘤细胞增殖的抑制活性，表明所述化合物能够抑制CDK8激酶，从而抑制肿瘤细胞的生长，达到抗肿瘤的作用。因此，可将本发明的化合物作为活性物与医药上可接受的载体制备成抗肿瘤药物治疗癌症。
本发明中术语“由CDK8介导的相关癌症”是指其中CDK8已成为必须基因的癌症。可通过耗竭细胞的CDK8表达来轻易地鉴定CDK8依赖性癌症并鉴定在其缺乏时至少部分被抑制的癌症。
本发明还提供一种药物，所述药物能够预防和/或治疗CDK8激酶介导的疾病，该药物的活性组分具有式(Ⅰ)所示结构的化学物或其药学上可接受的盐。
优选地，所述CDK8激酶介导的疾病选自以下疾病中的至少一种：卵巢癌、肺癌、食管鳞癌、结直肠癌、肝癌、子宫癌、胃癌。
优选地，所述药物剂型是片剂、胶囊、粉末剂、颗粒剂、混悬剂或注射剂。
需要的时候，在上述药物中还可以加入一种或多种药学上可接受的载体；所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体以及润滑剂等。
本发明的有益效果为：本发明通过采用分子对接软件MOE2019对含90多万小分子分子化合物的CHEMDIV数据库进行搜寻，分别采用药效团模拟、类药五规则以及分子对接进行逐级筛选，获得了含有通式(Ⅰ)所示结构的化合物。该化合物具有抑制CDK8激酶的作用，是发明人新发现的CDK8激酶抑制剂，且该化合物通过抑制CDK8激酶进一步抑制肿瘤细胞的生长，从而达到抑制肿瘤的作用。
具体实施方式
为了更加简洁明了的展示本发明的技术方案、目的和优点，下面结合具体实施例详细说明本发明的技术方案。
实施例1本发明化合物对肿瘤细胞的抑制作用
对本发明的式(Ⅱ)～(Ⅳ)的化合物进行了肿瘤细胞增殖抑制试验，试验方法采用常规的MTT法。具体操作如下：
细胞株:HO8910(人卵巢癌细胞)、HO8910-KO-MED12(敲除MED12的人卵巢癌细胞)、PC9(人肺癌细胞)、PC9-KO-MED12(敲除MED12的人肺癌细胞)、KYSE-150(人食管鳞癌细胞)、KYSE-180(人食管鳞癌细胞)、S1(人结直肠癌细胞)、S1-MI-80(过表达ABCG2的人结直肠癌细胞)
仪器：酶标仪(Model 550，Bio-Rad美国)
试验方法：用0.05％胰蛋白酶/EDTA消化原代癌细胞，3-5分钟后终止消化，收集细胞，1000rpm低速离心3-5分钟，用原代肿瘤细胞CF培养基制备成单细胞悬液，以每孔190μL细胞悬液接种于96孔板，细胞数为6000-8000个孔。培养24h后，每孔加10uL用DMSO溶解的含不同浓度药物的培养基。本发明中根据患者临床化疗方案选择奥沙利铂和氟尿嘧啶进行体外药敏实验。加药后在37℃继续培养68h后，每孔加入20μL 5mg/mL MTT，继续培养4h；小心吸去培养板中的培养液，每孔加入150μL的DMSO溶液，待甲瓒完全溶解后，用酶标仪测定各个孔的OD值。运用Bliss法计算IC50。试验结果如表1所示：
表1本发明化合物对肿瘤细胞增殖的抑制活性
| 肿瘤细胞IC<sub>50</sub>(μM) | 式(Ⅱ)化合物 | 式(Ⅲ)化合物 | 式(Ⅳ)化合物 |
| KYSE-150 | 2.63 | 2.28 | --- |
| KYSE-180 | 9.10 | >50 | --- |
| S1 | 0.65 | 0.53 | --- |
| S1-MI-80 | 8.92 | 4.86 | --- |
| HO8910 | --- | --- | 6.1 |
| HO8910-KO-MED12 | --- | --- | 5.62 |
| PC9 | --- | --- | 12.51 |
| PC9-KO-MED12 | --- | --- | 7.98 |
由表1可见，式(Ⅱ)～(Ⅳ)的化合物对肿瘤细胞增殖均具有较好的抑制效果，说明本发明化合物能抑制肿瘤细胞生长，具有抗肿瘤的作用。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (10)
1.一种如式(Ⅰ)所示结构的化合物或其可药用盐
其中：
R1为氢，或为1-4个碳原子的烷氧基，或为1-4个碳原子的烷基；
R2为氢，或为
或为
或为
2.如权利要求1所述的化合物，其特征在于，所述化合物选自以下几种化合物中的一种：
3.如权利要求1所述的化合物在制备CDK8激酶抑制剂中的应用。
4.如权利要求1所述的化合物在制备治疗癌症的药物中的应用。
5.如权利要求4所述的应用，其特征在于，所述癌症为由CDK8介导的相关的癌症。
6.如权利要求5所述的应用，其特征在于，所述癌症为卵巢癌、肺癌、食管鳞癌、结直肠癌、肝癌、子宫癌和/或胃癌。
7.一种CDK8激酶抑制剂，其特征在于，所述抑制剂为如权利要求1或2所述的化合物。
8.一种治疗肿瘤的药物组合，其特征在于，包含权利要求1或2所述的化合物。
9.如权利要求8所述的药物组合，其特征在于，还包括医学上可接受的载体，所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体以及润滑剂。
10.如权利要求8或9所述的药物组合，其特征在于，所述药物剂型是片剂、胶囊、粉末剂、颗粒剂、混悬剂或注射剂。
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| WO2011085129A2 (en) * | 2010-01-06 | 2011-07-14 | Errico Joseph P | Methods and compositions of targeted drug development |
| CN108743590A (zh) * | 2018-05-17 | 2018-11-06 | 中国药科大学 | 与vista具有亲和力的小分子化合物及其用途 |
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