CN114762691A - 双嘧达莫在抗肿瘤中的应用 - Google Patents
双嘧达莫在抗肿瘤中的应用 Download PDFInfo
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- CN114762691A CN114762691A CN202110037923.4A CN202110037923A CN114762691A CN 114762691 A CN114762691 A CN 114762691A CN 202110037923 A CN202110037923 A CN 202110037923A CN 114762691 A CN114762691 A CN 114762691A
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- Prior art keywords
- active ingredient
- pharmaceutically acceptable
- compound
- dipyridamole
- tumor
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Abstract
本发明涉及医药技术领域,具体地,涉及双嘧达莫在抗肿瘤中的应用。本发明公开了式(I)所示化合物(双嘧达莫)或其药学上可接受的盐或前药,在制备a)靶向Hsp90的抑制剂;b)抑制肿瘤细胞增殖的药物;c)预防和/或治疗肿瘤引起的相关疾病的药物中的应用。
Description
技术领域
本发明涉及医药技术领域,具体地,涉及双嘧达莫在抗肿瘤中的应用。
背景技术
二十世纪以来,人类的生活环境不断恶化,生活环境污染日趋加剧,人们与致癌因素的接触越来越紧密,恶性肿瘤的发病率也逐年递增,恶性肿瘤已经超过心脑血管疾病成为人类健康的最大敌人。根据世界卫生组织的实况报道,肿瘤即癌症已成为第二大致死原因,2012年有1400万人被诊断为癌症。据估计,到2023年,全球每年新增患癌病例将增至2200万,到2035年将增至2400万,即未来20年,癌症病例将增加约五成。报告数据显示,我国癌症新增病例和死亡病例位居全球之冠。因此,本领域迫切需要开发有效的抗肿瘤药物。
Hsp90的分子量约为90kDa,普遍存在于除古细菌外的原核和真核生物体内,研究工作表明真核生物细胞质中的Hsp90是维持生物体生存的必需元素。人源细胞质内Hsp90α的客户蛋白质包括了转录因子、磷酸激酶、DNA聚合酶等家族的众多成员,通过对客户蛋白质(如癌蛋白Raf-1、Akt、Src、Tert等)的调控,Hsp90α可在多个途径、多个环节影响肿瘤的发生和发展进程,Hsp90α是一个抗肿瘤药物研发的靶点。
作用于Hsp90 N端结构域ATP结合口袋的ATP结合抑制剂是以Hsp90为靶点的抗肿瘤药物研发的主攻方向,目前已有多个Hsp90 ATP结合抑制剂进入不同的临床研究阶段,然而,截至目前为止,尚未有Hsp90抑制剂成功获批上市。化合物的未达理想的药效以及诱发的热休克反应是导致这种结果的重要原因。所以,本领域迫切需要研发靶向Hsp90的新型抗肿瘤化合物。
发明内容
本发明的目的在于研发一种新型的不会诱发热休克反应的靶向Hsp90的抑制剂,从而抑制肿瘤细胞增殖,达到抗肿瘤的作用。具体地,本发明提供了双嘧达莫,其可以用于制备靶向Hsp90的抑制剂,从而有效抗肿瘤。
在本发明的第一方面,提供了一种活性成分或含所述活性成分的制剂的用途,所述活性成分为式(I)所示化合物或其药学上可接受的盐或前药,
并且所述活性成分或含所述活性成分的制剂被用于制备a)靶向Hsp90的抑制剂;b)抑制肿瘤细胞增殖的药物;c)预防和/或治疗肿瘤引起的相关疾病的药物。
在另一优选例中,所述肿瘤为Hsp90高表达相关的肿瘤。
在另一优选例中,所述肿瘤选自:结直肠癌、乳腺癌、非小细胞肺癌、神经胶质瘤或其组合。
在另一优选例中,所述制剂还包含选自下组的抗肿瘤药物:替泊替尼、恩曲替尼、达克替尼、劳拉替尼、瑞博西尼、来那替尼、玻玛西林、布吉替你、艾乐替尼、乐伐替尼、奥西替尼、帕博西尼、色瑞替尼、达拉非尼、阿法替尼、曲美替尼、克唑替尼、依维莫司、帕唑帕尼、拉帕替尼、厄洛替尼、吉非替尼、卡培他滨、奥沙利铂、曲氟尿苷复方片、或其组合。
在另一优选例中,所述活性成分或含所述活性成分的制剂用于制备以下一种或多用用途的药物:
(1)抑制Hsp90的生理功能;
(2)下调肿瘤细胞内Hsp90的客户蛋白的水平;所述客户蛋白选自下组:AKT、CDK4、CDK6、或其组合;
(3)不诱导产生细胞热休克反应。
在另一优选例中,所述制剂为口服的或者非口服的。
在另一优选例中,所述的制剂包括:粉剂、颗粒剂、胶囊剂、注射剂、酊剂、口服液、片剂、含片、或滴丸。
在本发明的第二方面,提供了一种药物组合物,包含:
i)作为第一活性成分的式(I)化合物或其药学上可接受的盐或其前药;
ii)作为第二活性成分的选自下组的其他抗肿瘤药物:替泊替尼、恩曲替尼、达克替尼、劳拉替尼、瑞博西尼、来那替尼、玻玛西林、布吉替你、艾乐替尼、乐伐替尼、奥西替尼、帕博西尼、色瑞替尼、达拉非尼、阿法替尼、曲美替尼、克唑替尼、依维莫司、帕唑帕尼、拉帕替尼、厄洛替尼、吉非替尼、卡培他滨、奥沙利铂、多西他赛、氟尿嘧啶、多柔比星、表柔比星、紫杉醇、环磷酰胺或甲氨蝶呤;
iii)其他药学上可接受的载体。
在本发明的第三方面,提供了一种第二方面所述的药物组合物的用途,用于制备:a)靶向Hsp90的抑制剂;b)抑制肿瘤细胞增殖的药物;c)预防和/或治疗肿瘤引起的相关疾病的药物。
在本发明的第四方面,提供了一种抑制Hsp90生理功能的方法,包括步骤:将医学有效量的式I化合物或其药学上可接受的盐或其前药或如第二方面所述的药物组合物和细胞充分接触,从而抑制Hsp90的生理功能。
在另一优选例中,所述细胞来源于哺乳动物,优选地为人。
在另一优选例中,所述细胞为Hsp90高表达的细胞。
在本发明的第五方面,提供了一种体外的非诊断性非治疗性的抑制肿瘤细胞增殖的方法,包括步骤:将所述细胞与医学有效量的式I化合物或其药学上可接受的盐或其前药或如第二方面所述的药物组合物充分接触,从而抑制肿瘤细胞增殖。
在另一优选例中,所述肿瘤选自下组:结直肠癌、乳腺癌、非小细胞肺癌、神经胶质瘤或其组合。
在另一优选例中,所述肿瘤细胞为Hsp90高表达的细胞。
在本发明的第六方面,提供了一种治疗肿瘤的方法,包括步骤:给有需要的对象施用医学有效量的式I化合物或其药学上可接受的盐或其前药或如第二方面所述的药物组合物。
在另一优选例中,所述对象为肿瘤患者。
在另一优选例中,所述肿瘤为Hsp90高表达的肿瘤。
在另一优选例中,所述肿瘤选自下组:结直肠癌、乳腺癌、非小细胞肺癌、神经胶质瘤或其组合。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1双嘧达莫与Hsp90之间的结合强度在μM水平。
图2双嘧达莫抑制A549、MCF7、SKBR3、U87、Ls174T与HCT116细胞的增殖生长。
图3双嘧达莫下调MCF7细胞中Hsp90客户蛋白AKT、CDK4、CDK6的水平。
具体实施方式
本发明人经过广泛而深入的研究,意外地发现双嘧达莫能有效靶向抑制Hsp90而抑制肿瘤细胞的增殖,在此基础上,完成了本发明。
具体地,本发明研究表明双嘧达莫通过抑制Hsp90的生理功能、下调Hsp90客户蛋白AKT、CDK4、CDK6等的水平,达到抑制肿瘤增殖的效果,因此双嘧达莫可以被用于制备Hsp90的抑制剂,和/或抗肿瘤的药物。
术语
如本文所用,“本发明的化合物”,“本发明的活性成分”,可互换使用,均指的是可以有效靶向抑制Hsp90的抑制剂双嘧达莫或其药学上可接受的盐。
双嘧达莫
双嘧达莫在临床上通常被应用为抗血栓和血管扩张药,可以抗血小板聚集,预防血栓形成。该药物具有磷酸二酯酶和腺苷转运体抑制活性,并因此提高细胞外腺苷水平,血管平滑肌和血小板中的cAMP/cGMP水平上升后,导致血管舒张以及血栓形成减少。此外,双嘧达莫还被证明具有潜在的抗氧化活性,因此在氧化应激相关的疾病中,例如中枢神经系统相关疾病和肿瘤等也存在潜在的使用价值。目前尚未有文献报道双嘧达莫通过作用于热休克蛋白Hsp90而对肿瘤细胞产生增殖抑制作用。
双嘧达莫具有如下式(I)所示的结构式:
本发明的活性成分
本发明的活性成分为式(I)所示的双嘧达莫或其药学上可接受的盐或其前药。
如本文所用,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。一类优选的盐是本发明化合物与碱形成的盐。适合形成盐的碱包括但并不限于:氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、磷酸钠等无机碱,氨水、三乙胺、二乙胺等有机碱。这些盐可通过已知的成盐方法由式(Ⅰ)的化合物制备。
药物组合物和施用方法
由于本发明化合物直接作用于热休克蛋白Hsp90,通过下调其客户蛋白质AKT、CDK4、CDK6等的水平抑制肿瘤细胞的增殖生长,因此,本发明化合物及其药学上可接受的无机或有机盐,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗Hsp90高表达相关的肿瘤。本发明的药物组合物包含安全有效量范围内的本发明化合物或其药学上可接受的盐及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有5-100mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选5~100mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明的主要优点包括:
(1)本发明首次揭示了双嘧达莫对热休克蛋白Hsp90的生理功能具有抑制作用,并且可以显著抑制A549、MCF7、SKBR3、U87、Ls174T与HCT116细胞的增殖生长。双嘧达莫为靶向热休克蛋白质Hsp90的药物研发提供了化合物结构骨架参考。
(2)双嘧达莫是已上市的药物,具有较好的抗肿瘤药物成药前景。
(3)双嘧达莫抑制Hsp90蛋白达到抗肿瘤效果的同时,不会诱发热休克反应,因此可以更有效的发挥治疗肿瘤的效果。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如Sambrook等人编写的《分子克隆:实验室手册》(New York:Cold Spring HarborLaboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
实施例1双嘧达莫与Hsp90存在中等强度的结合。
本实施例采用蛋白热稳定分析实验和等温滴定量热法(isothermal titrationcalorimetry,ITC)来确定双嘧达莫和Hsp90的体外结合作用以及结合强度。
1.1实验方法
蛋白热稳定分析实验使用VIIA7荧光定量PCR仪进行。实验中所用的缓冲体系为20mM Tris,75mM NaCl,1mMβ-mercaptoethanol,pH 7.4。实验体系中Hsp90N(Hsp90 N端结构域)的终浓度为10μM,双嘧达莫的终浓度为100μM,DMSO终浓度为5%,SYPRO Orange染料终浓度为5×。本实验以仅含5%DMSO和10μM蛋白质的样品作为对照。PCR程序设定如下:25℃,2min,温度上升速率为1.6℃/s;25℃~99℃,温度上升的速率为0.05℃/s,升温过程中同时记录荧光值变化;99℃,2min,随后结束实验。得到的数据用GraphPad Prism 5进行处理分析,计算蛋白质的热变性温度。
等温滴定量热(ITC)实验于30℃的条件下在MicroCal iTC200中进行。实验使用缓冲体系为20mM Tris,75mM NaCl,6mM MgCl2,1mMβ-mercaptoethanol,pH 7.4。实验过程中,将1.5mM Hsp90N(Hsp90 N端结构域)逐滴滴入到50μM的双嘧达莫中,首滴液体体积为0.4μL,接下来19滴液滴体积为2μL,每滴时间间隔为120s,总的滴定时间为40min。本实验中,DMSO的终浓度为2.5%。实验数据用Origin 7.0进行处理分析。
1.2实验结果
测试结果如图1所示。从图1A中,我们可以看到与双嘧达莫结合后,Hsp90N的热变性温度提高了2.16℃,这在分子水平证明了双嘧达莫能够与Hsp90 N端结构域发生相互作用,并因此提高Hsp90 N端结构域的热稳定性。
图1B进一步确定了双嘧达莫与Hsp90N之间具有特异性相互作用,其结合解离常数为4.27±0.55μM。
实施例2双嘧达莫对肿瘤细胞增殖生长的抑制效果测试方法及结果
本实施例采用SRB法测定双嘧达莫对肿瘤细胞的增殖生长抑制效果。
2.1实验方法
将状态良好的处于对数生长期的A549、MCF7、SKBR3、U87、Ls174T与HCT116细胞消化,计数。以培养液稀释到一定浓度,混匀。以排枪接种到96孔板中心的60个孔中,每孔200μL。周围一圈加无菌超纯水,每孔200μL。除SKBR3细胞外(8000个/孔),其它细胞每孔细胞数5000-6000个。随后,将细胞在37℃、5%CO2饱和湿度培养箱中培养24h。
化合物配制,双嘧达莫用培养液梯度稀释,使加入96孔板双嘧达莫的终浓度分别为1,5,10,20,40,60和80μM,DMSO含量为0.5%。每个浓度设三个复孔,以涡旋振荡器混匀或用枪吹打混匀。弃培养基,将用培养基稀释的化合物加入96孔板,每孔200μL。对照孔加入200μL含DMSO的培养液。于37℃、5%CO2饱和湿度培养箱中培养72h。
72h之后,以水1:1稀释100%(wt/vol)三氯乙酸,混匀后加入到96孔板中,每孔50μL,对细胞进行固定。于4℃冰箱中放置1h。固定之后,倒掉96孔板中液体,并以缓慢流动的自来水倾斜冲洗4次。于烘箱中烘干。
将冰醋酸以自来水稀释到1%(vol/vol)。以1%冰醋酸配制SRB,浓度为4mg/ml,混匀,放置至SRB完全溶解。96孔板每孔加入100μL SRB溶液,放置15min,进行染色。15min后以1%冰醋酸冲洗4次以冲洗掉多余未结合的SRB染料。于烘箱中烘干。
96孔板中每孔加入150μL 10mM Tris溶液,在微孔板快速振荡器上振荡直至SRB充分溶解。在酶标仪上510nm波长下读取OD值。
计算化合物对细胞的抑制率,计算公式为:
%growthinhibition=100-%of control cell growth
2.2实验结果
测试结果如图2所示:双嘧达莫能够抑制A549、MCF7、SKBR3、U87、Ls174T与HCT116细胞的增殖生长,n=3。
实施例3双嘧达莫在细胞环境下与Hsp90蛋白质发生相互作用,通过对Hsp90的抑制作用,降低MCF7细胞中Hsp90客户蛋白AKT、CDK4、CDK6含量的检测方法及结果。
本实施例采用免疫印迹法检测双嘧达莫对MCF7细胞中Hsp90客户蛋白AKT、CDK4和CDK6以及热休克反应蛋白Hsp70的影响。
本实施例中所使用的抗体信息如下所示:
Anti-Hsp90(R&D systems,#341320,1:2000),Anti-Hsp70(Cell SignalingTechnology,#4872,1:1000),Anti-AKT(Cell Signaling Technology,#9272,1:1000),Anti-CDK4(Cell Signaling Technology,#12790,1:1000),Anti-CDK6(Cell SignalingTechnology,#3136,1:2000),Anti-GAPDH(Cell Signaling Technology,#2118,1:1000)。
Hsp90和CDK6的一抗为鼠源抗体,Hsp70、AKT、CDK4和GAPDH一抗为兔源抗体。本实施例中所使用的二抗Anti-Rabbit购于Absin公司,按1:4000的稀释比例配置使用;Anti-mouse购于Cell Signaling Technology公司,稀释比例为1:2000。
具体实验方法与步骤如下:
3.1双嘧达莫在细胞环境下与Hsp90蛋白质发生相互作用:
将状态良好的MCF7细胞用胰酶消化,然后加入细胞培养液终止消化并重悬细胞,接着,于300g离心5min收集细胞。收集的细胞用PBS缓冲液洗涤三次,除去多余的胰酶及培养液,最后用含PMSF的PBS缓冲液重悬。
PBS缓冲液重悬后的细胞于液氮中反复冻融三次,冻融结束后,在4℃的条件下,20000g离心20min收集上清。细胞裂解上清用80μM的双嘧达莫和1%DMSO室温下处理20min。
处理完成后,将细胞等分到PCR管中,并在不同的温度下孵育5min,处理温度从49℃开始,3℃一个阶梯,最高温度为70℃。加热变性后的细胞裂解液在室温放置5min后,于4℃,20000g离心20min分离上清和沉淀。上清加5×的上样缓冲液,于100℃加热10min后,用蛋白免疫印迹实验检测上清中的Hsp90蛋白质。
3.2双嘧达莫对肿瘤细胞中Hsp90客户蛋白以及细胞热休克反应标志蛋白Hsp70的影响:
为了验证双嘧达莫对Hsp90客户蛋白的调控作用,以及化合物是否诱发细胞产生了热休克反应,我们对双嘧达莫处理后的细胞进行了蛋白含量变化的检测。
(1)将状态良好且处于生长对数期的MCF7细胞用胰酶消化,混合均匀后接种到12孔板中,置于37℃,5%CO2培养箱中继续培养。
(2)等到细胞密度生长至约70%,弃培养基,加入含有20μM、40μM、60μM双嘧达莫或100nM AUY922和0.1%DMSO的培养基。
(3)药物处理48h后,收集细胞。贴壁细胞首先用PBS缓冲液清洗两次,然后加入80μL RIPA裂解液(含1mM PMSF)裂解细胞,细胞完成裂解后于20000g,4℃,离心20min,收集上清。用Bradford试剂盒测定细胞裂解液总蛋白浓度,根据结果调整样品浓度,使样品浓度保持一致,最后,加入5×上样缓冲液,100℃下煮沸10min,待蛋白免疫印迹实验检测结果。
3.3蛋白质免疫印迹实验:
(1)SDS-PAGE
将制备好的样品离心后,用移液枪将样品加入各孔道,每孔上样10μL,蛋白Marker上样3μL,剩余体积用上样缓冲液补齐。电泳条件如下:60V积层低电压运行~30min,使样品在层积胶中浓缩成线;再以120V分离电压较快分离样品,待溴酚蓝移动至分离胶底部时,结束电泳;
(2)转膜
用甲醇浸湿PVDF膜完成膜活化,接着将PVDF膜放入转膜液,除去膜表面多余的甲醇。装配转膜三明治:将黑白夹的黑面置于底部,从负极到正极按照海绵片-滤纸-胶-PVDF膜-滤纸-海绵片的顺序制备三明治夹。为避免气泡产生,整个三明治夹制备过程在转膜液中进行。转膜槽中加入低温保存的转膜液和冰盒,防止转膜过程温度过高,恒流0.26A转膜2h。转膜完成后,剪裁含目的蛋白条带的PVDF膜,做好标记,于孵育盒中孵育;
(3)抗体孵育与显影
用TBST缓冲液清洗含有目的蛋白条带的PVDF膜,并置于含5%脱脂牛奶的TBST缓冲液中,缓慢振荡,封闭1h。弃封闭液,用TBST缓冲液振荡清洗3次,每次10min。蛋白质一抗用一抗稀释液按比例稀释。清洗干净的PVDF膜中加入相应的一抗,4℃摇晃孵育过夜。弃一抗,加适量的TBST清洗3次,每次洗涤10min,去除非特异性结合的抗体。二抗稀释于含5%脱脂牛奶的TBST缓冲液中。根据一抗的种属来源选择相应的二抗并与PVDF膜室温孵育1h。弃二抗,加入适量的TBST缓冲液清洗3次,每次洗涤10min,去除非特异性结合的抗体。用化学发光法检测显影。
3.4实验结果
实验结果如图3所示:双嘧达莫能够在细胞环境中与Hsp90蛋白质发生相互作用,使MCF7细胞中Hsp90的客户蛋白AKT、CDK4和CDK6的含量降低,并且不引发细胞产生热休克反应。
图3A中我们可以看到,在结合双嘧达莫后,Hsp90蛋白质的热稳定性提高,表明化合物的存在对蛋白质具有热保护作用。图3B中显示,随着双嘧达莫使用量的增加,Hsp90客户蛋白AKT、CDK4和CDK6的含量逐渐下降,与此同时细胞中Hsp70的含量并没有随着双嘧达莫使用量的增加而发生明显改变。与阳性化合物AUY922相比,双嘧达莫对AKT、CDK4和CDK6影响相对较弱,但是AUY922明显引起了细胞中Hsp70含量的增加,这也是包括AUY922在内的Hsp90临床抑制剂一直未能上市的原因之一。基于以上发现,本发明化合物有望开发成为靶向Hsp90的抗肿瘤先导化合物或药物。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (9)
2.如权利要求1所述的用途,其特征在于,所述制剂还包含选自下组的抗肿瘤药物:替泊替尼、恩曲替尼、达克替尼、劳拉替尼、瑞博西尼、来那替尼、玻玛西林、布吉替你、艾乐替尼、乐伐替尼、奥西替尼、帕博西尼、色瑞替尼、达拉非尼、阿法替尼、曲美替尼、克唑替尼、依维莫司、帕唑帕尼、拉帕替尼、厄洛替尼、吉非替尼、卡培他滨、奥沙利铂、曲氟尿苷复方片、或其组合。
3.如权利要求1所述的用途,其特征在于,所述活性成分或含所述活性成分的制剂用于制备以下一种或多用用途的药物:
(1)抑制Hsp90的生理功能;
(2)下调肿瘤细胞内Hsp90的客户蛋白的水平;所述客户蛋白选自下组:AKT、CDK4、CDK6、或其组合;
(3)不诱导产生细胞热休克反应。
4.如权利要求1所述的用途,其特征在于,所述制剂为口服的或者非口服的。
5.一种药物组合物,其特征在于,包含:
i)作为第一活性成分的式(I)化合物或其药学上可接受的盐或其前药;
ii)作为第二活性成分的选自下组的其他抗肿瘤药物:替泊替尼、恩曲替尼、达克替尼、劳拉替尼、瑞博西尼、来那替尼、玻玛西林、布吉替你、艾乐替尼、乐伐替尼、奥西替尼、帕博西尼、色瑞替尼、达拉非尼、阿法替尼、曲美替尼、克唑替尼、依维莫司、帕唑帕尼、拉帕替尼、厄洛替尼、吉非替尼、卡培他滨、奥沙利铂、多西他赛、氟尿嘧啶、多柔比星、表柔比星、紫杉醇、环磷酰胺或甲氨蝶呤;
iii)其他药学上可接受的载体。
6.一种如权利要求5所述的药物组合物的用途,其特征在于,用于制备:a)靶向Hsp90的抑制剂;b)抑制肿瘤细胞增殖的药物;c)预防和/或治疗肿瘤引起的相关疾病的药物。
7.一种抑制Hsp90生理功能的方法,其特征在于,包括步骤:将医学有效量的式I化合物或其药学上可接受的盐或其前药或如权利要求5所述的药物组合物和细胞充分接触,从而抑制Hsp90的生理功能。
8.一种体外的非诊断性非治疗性的抑制肿瘤细胞增殖的方法,其特征在于,包括步骤:将所述细胞与医学有效量的式I化合物或其药学上可接受的盐或其前药或如权利要求5所述的药物组合物充分接触,从而抑制肿瘤细胞增殖。
9.一种治疗肿瘤的方法,其特征在于,包括步骤:给有需要的对象施用医学有效量的式I化合物或其药学上可接受的盐或其前药或如权利要求5所述的药物组合物。
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