CN101511179A - Stat3的小分子抑制剂及其用途 - Google Patents
Stat3的小分子抑制剂及其用途 Download PDFInfo
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- CN101511179A CN101511179A CNA2006800123753A CN200680012375A CN101511179A CN 101511179 A CN101511179 A CN 101511179A CN A2006800123753 A CNA2006800123753 A CN A2006800123753A CN 200680012375 A CN200680012375 A CN 200680012375A CN 101511179 A CN101511179 A CN 101511179A
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Abstract
本发明涉及作为Stat3抑制剂的小分子。本发明还涉及这些化合物在诱导细胞死亡,和增加细胞对抗癌药引起的细胞死亡的敏感性中的用途。
Description
[0001]本申请请求享有2005年2月25日提交的美国临时申请系列第60/656,597号的权益,其被引入本文作为参考。
[0002]本申请是许可号为DOD BC023370的基金,NIH支持号为CA096714,和乳腺癌防卫部(Department of Defense Breast Cancer)许可号为DAMD17-03-1-0508的一部分。政府在本发明中可享有一定的权力。
发明背景
发明领域
[0003]本发明属于药物化学领域。尤其是,本发明涉及作为Stat3抑制剂的小分子。本发明还涉及这些化合物在诱导细胞死亡,和增加细胞对抗癌药引起的细胞死亡的敏感性中的用途。
相关技术
[0004]侵袭性癌细胞表型是各种遗传和后天改变的结果,这会导致细胞内信号途径的反常(Ponder,Nature 411:336(2001))。然而,所有癌细胞的共同点是它们不能执行凋亡程序,由于正常凋亡机制缺陷而导致的缺乏适当的凋亡程序是癌症的标志(Lowe等,Carcinogenesis 21:485(2000))。目前癌症的大部分治疗,包括化疗剂、放射和免疫治疗,都是通过间接诱导癌细胞凋亡而起作用的。因此,由于正常凋亡机制缺陷而导致的癌细胞不能执行凋亡程序通常与对化疗、放射或免疫治疗引起的凋亡的抵抗增加有关。由于凋亡缺陷而导致的不同来源的人类癌症对目前治疗方案的主要抵抗或获得性抵抗是目前癌症治疗的主要问题(Lowe等,Carcinogenesis 21:485(2000);Nicholson,Nature 407:810(2000))。因此,目前和将来对设计和开发新的分子靶向的特异性抗肿瘤疗法以改善癌症患者的生存和生活质量所作的努力必须包括对抵抗凋亡的癌细胞有特异性靶向作用的策略。因此,以在直接抑制癌细胞凋亡中起主要作用的关键负调节子为作用靶点代表了设计新抗癌药物的很有希望的治疗策略。
[0005]信号传导与转录活化因子(STATs)响应细胞因子和生长因子而被激活(Darnell等,Science 264:1415(1994))。JAKs、Src和表皮生长因子受体(EGFR)是Stat3的上游调节子(Bromberg等,Mol.Cell.Biol.18:2553(1998);Sartor等,Cancer Res.57:978(1997);Garcia等,Oncogene 20:2499(2001))。Stat3蛋白的主要结构域包括N-端的四聚体和亮氨酸拉链,DNA结合域,和羧基端的SH2激活区。SH2区负责Stat3与酪氨酸-磷酰化受体的结合和对DNA结合和基因表达很必要的二聚作用(Zhong等,Science 264:95(1994))。Stat3被Y-705的磷酸化所激活,这导致二聚体形成,核易位,Stat3特异的DNA结合元素的识别,和靶基因转录的激活(Darnell等,Science264:1415(1994);Zhong等,Science 264:95(1994))。
[0006]在乳腺癌细胞系中经常检测到Stat3的构成激活,而在正常乳腺上皮细胞中则检测不到(Garcia等,Cell.Growth.Differ.8:1267(1997);Bowman等,Oncogene 19:2474(2000))。已经报道了大约有60%的乳腺肿瘤含有持续激活的Stat3(Dechow等,Proc.Natl.Acad.Sci.USA 101:10602(2004))。Stat3已经被分类为原癌基因,这是因为Stat3可以在培养细胞中介导致癌性转化和在裸鼠中介导肿瘤形成(Bromberg等,Cell 98:295(1999))。Stat3可能通过刺激细胞增殖、促进血管发生、和对由常规治疗引起的凋亡产生耐药性而参与肿瘤生成(Catlett-Falcone等,Curr.Opin.Oncol.11:1(1999);Catlett-Falcone等,Immunity 10:105(1999);Alas等,Clin.Cancer Res.9:316(2003);Wei等,Oncogene 22:1517(2003))。Stat3通过它来促进肿瘤生成的可能存在的下游靶包括上调抗凋亡因子(Bcl-2、存活素、Mcl-1和Bcl-XL),细胞周期调节子(cyclin D1、MEK5和c-myc),和肿瘤血管发生诱导物(VEGF)(Bromberg等,Cell 98:295(1999);Wei等,Oncogene 22:1517(2003);Real等,Oncogene 21:7611(2002);Puthier等,Eur.J.Immunol.29:3945(1999);Niu等,Oncogene 21:2000(2002);Kiuchi等,J.Exp.Med.189:63(1999);Song等,Oncogene(2004))。激活的Stat3信号直接促成癌症的恶性进展。Stat3致癌功能通过前存活蛋白(pro-survival proteins)如存活素、Mcl-1、Bcl-2和Bcl-XL而起作用,并导致阻碍凋亡(Real等,Oncogene 21:7611(2002);Aoki等,Blood 101:1535(2003);Epling-Burnette等,J.Clin.Invest.107:351(2001);Nielsen等,Leukemia 13:735(1999))。阻断Stat3信号抑制癌细胞生长,这证明了Stat3对于肿瘤细胞的存活或生长是至关重要的(Alas等,Clin.Cancer Res.9:316(2003);Aoki等,Blood 101:1535(2003);Epling-Burnette等,J.Clin.Invest.107:351(2001);Burke等,Oncogene 20:7925(2001);Mora等,Cancer Res.62:6659(2002);Ni等,Cancer Res.60:1225(2000);Rahaman等,Oncogene 21:8404(2002))。
[0007]由于Stat3经常在乳腺癌中激活(Dechow等,Proc.Natl.Acad.Sci.USA 101:10602(2004)),因此有可能通过抑制乳腺癌异常生长,而将它作为癌症治疗的有吸引力的靶点。基于肽的Stat3抑制剂,它模拟Stat3 SH2区互补结合结构,被报道在体外成功地阻断了Stat3功能(Turkson等,J.Biol.Chem.276:45443(2001))。也已经尝试去抑制Stat3上游调节子,如Janus激酶,尤其是JAK2(Blaskovich等,Cancer Res.63:1270(2003)。已经公开了Stat3同型二聚体的高分辨率X-射线三维结构(Becker等,Nature 394:145(1998))。根据Stat3的X-射线结构,需要开发具有高细胞渗透性和稳定性,且直接阻断Stat3活性的Stat3小分子抑制剂。
发明概述
[0008]公认的是,癌细胞或其支持细胞失去由于基因损伤或者暴露于凋亡诱导剂(如抗癌剂和辐射)而经历凋亡的能力是癌症发生和进展的主要原因。认为在癌细胞或其支持细胞(如肿瘤脉管系统中的新生血管细胞)中诱发凋亡是目前市场上销售的或处于实验过程中的实际上所有有效癌症治疗药或放射疗法的普遍作用机制。细胞不能经历凋亡的一个原因是Stat3的活性增加,这至少要部分归因于Stat3上调了抗凋亡因子和/或改变了细胞周期调节的能力。
[0009]本发明打算将患有癌症的动物暴露于治疗有效量的药物(例如小分子),该药物通过抑制Stat3和异源结合配体之间的相互作用和/或从SH2激活区抑制Stat3的同二聚体形成来降低Stat3功能,这种暴露将彻底抑制癌细胞或支持细胞生长和/或使该细胞群对癌症治疗药或放射疗法诱导细胞死亡的活性更加敏感。本发明预期Stat3抑制剂可满足对于多种癌症的治疗所未能满足的需求,不论是作为单一疗法施用诱导癌细胞凋亡和/或细胞周期停滞,还是在与其它诱导细胞死亡的癌症治疗药或放射疗法的临时关系中进行给药(联合疗法),以使更大比例的癌细胞或支持细胞对执行凋亡程序敏感,相对于只用癌症治疗药物或单独用放射疗法治疗的动物中相应比例的细胞而言。
[0010]在本发明的某些实施方案中,用治疗有效量的本发明化合物和抗癌剂或放射疗程联合治疗动物会在这些动物中产生更大的肿瘤响应和临床益处,相对于单独用该化合物或抗癌剂/放射治疗的那些动物而言。另外,由于该化合物会降低所有细胞的凋亡阈值,因此响应抗癌剂/放射线的凋亡诱导活性而成功地执行凋亡程序的细胞比例将会加大。可选择地,本发明化合物将用于更低剂量、从而更小毒性和更大耐受性的抗癌剂和/或放射线的给药,以产生与常规剂量抗癌剂/放射线单独给药相同的肿瘤响应/临床益处。由于所有已批准的抗癌剂和放射治疗的剂量都是已知的,因此本发明关注于它们与本发明化合物的不同组合。另外,由于本发明化合物可至少部分通过抑制Stat3的抗凋亡活性和/或细胞周期改变活性而起作用,因此癌细胞和支持细胞暴露于治疗有效量的该化合物将暂时与细胞响应抗癌剂或放射疗法而执行凋亡程序同时进行。因此,在一些实施方案中,本发明组合物与某些临时关系联合给药提供了特别有效的治疗实践。
[0011]本发明涉及对抑制Stat3活性和增加细胞对凋亡和/或细胞周期停滞诱导剂敏感性有用的化合物。在一个特定实施方案中,化合物是STA-21或其衍生物、类似物、前药或药学可接受的盐。
[0012]在一个实施方案中,Stat3活性抑制剂选自化合物1(STA-21),以及表示为化合物2和3的类似物组成的组。
[0013]本发明涉及用STA-21表示的化合物或其衍生物、类似物、前药或药学可接受的盐,它是Stat3活性抑制剂。本发明涉及本发明化合物在抑制具有增加的Stat3活性的细胞生长中的应用。本发明进一步涉及本发明化合物在具有增加的Stat3活性的细胞中诱导细胞周期停滞和/或凋亡的应用。本发明还涉及本发明化合物在增加细胞对凋亡和/或细胞周期停滞诱导剂的敏感性中的应用。该化合物对治疗、改善或预防与Stat3活性增加有关的疾病是有用的。该化合物还用于治疗、改善或预防响应诱导凋亡细胞死亡的疾病,例如以凋亡失调为特征的疾病,包括过度增殖性疾病,如癌症和银屑病。在某些实施方案中,该化合物可以用于治疗、改善或预防以抵抗癌症治疗为特征的癌症(例如化学抵抗、放射抵抗、激素抵抗等的那些癌症)。在其它实施方案中,该化合物可以用于治疗过度增殖性疾病和以Stat3活性增加为特征的其它病症。
[0014]本发明提供了含有诱导细胞凋亡或使细胞对凋亡诱导剂敏感的治疗有效量的STA-21或其衍生物、类似物、前药或药学可接受的盐的药物组合物。
[0015]本发明进一步提供了含有STA-21或其衍生物、类似物、前药或药学可接受的盐以及对动物施用该化合物的说明书的药盒。该药盒可任选含有其它治疗剂,如抗癌剂、凋亡调节剂。
绘图/附图的简要说明
[0016]本发明或申请文件含有至少一张用颜色绘制的附图。该带彩色附图的专利或专利申请公开文本的副本将通过提出请求和支付必要的费用由专利局提供。
[0017]图1A-1D显示了基于结构的虚拟数据筛选的模型示意图。(A)STAT3β蛋白的SH2区二聚体形成界面。结构基于PDB entry 1BG1。这两个SH2区颜色不同。圆形区域表示用于虚拟筛选研究的靶PTR结合位点。(B)STA-21对STAT3β SH2区的预期结合模型。STA-21用球棍模型表示。STAT3β SH2区的分子表面用静电势着色:红色表示正电荷最多的区域,蓝色表示负电荷最多的区域。(C)STAT3β SH2区和STA-21之间形成的特殊氢键。用DOCK程序预期结合模型。只有与STA-21形成氢键的残基显示在明显的原子模型中。(D)STA-21结构。所有图片都是用Sybyl程序产生的。
[0018]图2A-2B显示了STA-21对癌细胞中Stat3依赖性萤光素酶活性的抑制。(A)将被pLucTKS3 Stat3-依赖性萤光素酶受体稳定转染的Caov-3癌细胞的克隆用于启动Sat3小分子抑制剂筛选。用20μM STA-21以及其它小分子化合物处理克隆细胞48h,然后采集细胞进行萤光素酶活性分析。(B)用20μMSTA-21处理被pLucTKS3 Stat3-依赖性萤光素酶受体或SV40萤光素酶受体稳定转染的MDA-MB-435s细胞的克隆48h。根据制造商的说明,用Promega萤光素酶试剂盒检测萤光素酶活性。结果基于三个独立实验的平均数和标准差。
[0019]图3A-3B显示了STA-21对Stat3DNA结合活性和Stat3-调节的抗凋亡因子的抑制。(A)在室温下用30μM STA-21培养MDA-MB-435s细胞核提取物30min,然后用r-32P-ATP标记的-致结合序列室温培养20min。将反应混合物在8%聚丙烯酰胺凝胶上分离开。(B)将来自经标示浓度STA-21处理了48h的MDA-MB-468细胞的溶胞产物在10%SDS-PAGE上分离开,然后按照说明用抗体进行免疫印迹。
[0020]图4A-4B显示了STA-21抑制在组成上具有Stat3信号的乳腺癌细胞的存活,但不抑制在组成上不具有Stat3信号的乳腺癌细胞的存活。(A)不同细胞系中Y-705处的Stat3磷酸化。(B)按照说明的浓度用STA-21处理细胞系48h,然后采集细胞,并分析Sub-G1曲线,该曲线在FACScan流式细胞仪(Becton Dickinson,San Jose,CA)上可指示凋亡细胞。结果基于三个独立实验的平均数和标准差。
[0021]图5A-5H显示STA-21抑制乳腺癌细胞Stat3易位和二聚体形成。(A)未转染和未经处理的MDA-MB-435s细胞。(B和E)用抗-flag IgG-罗丹明将被pCMV-Stat3-Flag和pCMV-Stat3-HA质粒共转染的细胞免疫染色。(B)未经处理的细胞和(E)STA-21处理的细胞。(C和F)用抗-HAIgG-FITC将转染的细胞免疫染色。(C)未经处理的细胞和(F)STA-21处理的细胞。(D和G)用抗-HAIgG-FITC和抗-flagIgG-罗丹明将转染的细胞共同免疫染色。(D)未经处理的细胞显示亮橙色。(G)STA-21处理的细胞显示淡橙色和单独的绿色和红色。(H)MDA-MB-435s细胞被pCMV-Stat3-Flag和pCMV-Stat3-HA质粒共转染,并暴露于20μMSTA-21 24h,然后用抗-HA或抗-Flag抗体使细胞溶胞产物免疫沉淀。在10%SDS-PAGE上将免疫沉淀物拆分,然后用抗-HA、抗-Flag或抗-Stat3抗体进行免疫印迹。
发明的详细说明
[0022]本发明涉及作为Stat3活性抑制剂的STA-21或其衍生物、类似物、前药或药学可接受的盐。通过抑制Stat3,这些化合物抑制具有增加的Stat3活性的细胞的细胞生长。这些化合物也增加细胞对凋亡和/或细胞周期停滞诱导剂的敏感性,在一些情况下,它们本身也会引起凋亡和/或细胞周期停滞。因此,本发明涉及抑制细胞生长的方法,增加细胞对凋亡和/或细胞周期停滞诱导剂敏感性的方法,和诱导细胞凋亡和/或细胞周期停滞的方法,包括将细胞与STA-21或其衍生物、类似物、前药或药学可接受的盐单独接触,或连同凋亡诱导剂一起接触。本发明进一步涉及治疗、改善或预防动物病症的方法,该病症与增加的Stat3活性有关或响应诱导凋亡,包括给动物施用STA-21或其衍生物、类似物、前药或药学可接受的盐和任选的凋亡诱导剂。这些病症包括以凋亡失调为特征的那些病症,和以具有增加的Stat3活性的细胞增殖为特征的那些病症。
[0023]在一个实施方案中,Stat3活性抑制剂选自化合物1(STA-21)、2和3。
[0024]术语“抗癌剂”和“抗癌药”当用于本文中时,指的是用于过度增殖性疾病如癌症(例如在哺乳动物中)治疗的任何治疗剂(例如化疗化合物和/或分子治疗化合物)、反义疗法、放射疗法或手术干预。
[0025]术语“前药”当用于本文中时,指的是母体“药物”分子的药理学无活性的衍生物,它在目标生理学体系中需要进行生物转化(例如自发的或酶的),以释放或将前药转化(例如酶的、机械的、电磁的)成活性药物。设计前药以克服与稳定性、毒性、缺乏特异性或有限的生物利用度有关的问题。示例性的前药包括活性药物分子本身和化学修饰基团(例如可逆地隐藏药物活性的基团)。一些优选的前药是在代谢条件下具有可裂解基团的化合物的变体或衍生物。示例性的前药在体内或体外变得有药学活性,当它们在生理条件下进行溶剂分解或进行酶解或其它生化转化(例如磷酸化、氢化、脱氢、糖基化)时。前药经常提供溶解度、组织相容性或哺乳动物器官内延迟释放方面的优点(参见例如Bundgard,Design of Prodrugs,pp.7-9,21-24,Elsevier,Amsterdam(1985);和Silverman,The Organic Chemistryof Drug Design and Drug Action,pp.352-401,Academic Press,San Diego,CA(1992))。通常的前药包括酸衍生物,如将母体酸与适当的醇(例如低级醇)反应制得的酯,将母体酸化合物与胺反应制得的酰胺,或与碱性基团反应形成酰化的碱衍生物(例如低级酰胺)。
[0026]术语“药学可接受的盐”当用于本文中时,指的是在目标动物(例如哺乳动物)中生理学耐受的本发明化合物的任何盐(例如通过与酸或碱反应而获得的)。本发明化合物的盐可衍生自无机或有机酸和碱。酸的实例包括但不限于盐酸、氢溴酸、硫酸、硝酸、高氯酸、富马酸、马来酸、磷酸、羟乙酸、乳酸、水杨酸、琥珀酸、对甲苯磺酸、酒石酸、乙酸、柠檬酸、甲磺酸、乙磺酸、甲酸、苯甲酸、丙二酸、磺酸、萘-2-磺酸和苯磺酸等。其它酸,如草酸,虽然它们本身不是药学可接受的,但也可用于制备作为中间体有用的盐,以获得本发明化合物及其药学可接受的酸加成盐。
[0027]碱的实例包括但不限于碱金属(例如钠)氢氧化物,碱土金属(例如镁)氢氧化物,铵,和式NW4 +化合物,其中W是C1-4烷基等。
[0028]盐的实例包括但不限于:醋酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、重硫酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、flucoheptanoate、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、氯化物、溴化物、碘化物、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、palmoate、果胶脂酸盐(pectinate)、过硫酸盐、苯丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一酸盐等。盐的实例包括本发明化合物阴离子与适当的阳离子如Na+、NH4 +和NW4 +(其中W是C1-4烷基)等化合形成的盐。为了治疗有用,本发明化合物的盐打算是药学可接受的。然而,非药学可接受的酸和碱的盐也可找到用处,例如,在制备或纯化药学可接受的化合物中使用。
[0029]术语“治疗有效量”当用于本文中时,指的是足以导致病症的一个或多个症状改善、或防止病症进行、或引起病症退化的治疗剂的量。例如,关于癌症的治疗,治疗有效量优选指的是降低肿瘤生长速度、减少肿瘤块、减少转移的数量、增加进行性肿瘤的时间、或延长存活期至少5%、优选至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%或至少100%的治疗剂的量。
[0030]术语“使敏感(sensitize)”和“增加敏感(sensitizing)”当用于本文中时,指的是通过施用第一治疗剂(例如式I化合物),使动物或动物的细胞对第二治疗剂的生物效应(例如促进或延迟细胞功能的某个方面,包括但不限于细胞生长、增殖、侵入、血管发生或凋亡)更敏感或更易起反应。第一治疗剂对靶细胞的增敏效果可以通过施用第二治疗剂连同或不连同施用第一治疗剂所观察到的预期生物效应(例如促进或延迟细胞功能的某个方面,包括但不限于细胞生长、增殖、侵入、血管发生或凋亡)之间的区别来衡量。在缺乏第一治疗剂响应的情况下,增敏细胞的响应可以增加至少10%、至少20%、至少30%、至少40%、至少50%、至少60%、至少70%、至少80%、至少90%、至少100%、至少150%、至少200%、至少250%、至少300%、至少350%、至少400%、至少450%或至少500%。
[0031]术语"凋亡失调"当用于本文中时,指的是细胞经由凋亡而经历细胞死亡的能力(例如遗传因素)的任何畸变。凋亡失调与多种病症有关或由多种病症引起,包括例如自身免疫性疾病(例如系统性红斑狼疮、类风湿性关节炎、移植物抗宿主疾病、重症肌无力或综合征),慢性炎症性疾病(例如银屑病、哮喘或克罗恩病),过度增殖性疾病(例如肿瘤、B细胞淋巴瘤或T细胞淋巴瘤),病毒感染(例如疱疹、乳头状瘤或HIV),和其它病症,如骨关节炎和动脉粥样硬化。应当注意的是,当失调是由病毒感染引起或与病毒感染有关时,在失调发生时或观察到失调时有可能检测到病毒感染,也可能检测不到。也就是说,即使在病毒感染的症状消失以后,病毒引起的失调也可以发生。
[0032]术语"Stat3"当用于本文中时,指的是本领域技术人员已知的Stat3的任何形式,包括但不限于Stat3α和Stat3β。
[0033]术语"具有增加的Stat3活性的细胞"当用于本文中时,指的是其中Stat3被组成性激活的细胞(例如磷酸化),或与正常(即非患病的)细胞相比,其中Stat3被激活更长时间或更大程度的细胞。
[0034]术语"其衍生物或类似物"当用于本文中与STA-21有关时,指的是抑制Stat3活性和以STA-21的总体结构为基础的任何化合物。
[0035]术语“过度增殖性疾病”当用于本文中时,指的是其中动物增殖细胞的某个局部群体不受正常生长的通常限制支配的任何病症。过度增殖性疾病的实例包括肿瘤、赘生物和淋巴瘤等,和非癌疾病,如自身免疫性疾病(例如银屑病)。据说如果赘生物不侵入或转移的话,它就是良性的,如果它发生侵入或转移,就是恶性的。“转移”细胞的意思是细胞可以侵入和破坏相邻的身体结构。增生是细胞增殖的一种形式,包括组织或器官中细胞数量增多,而不显著改变结构或功能。化生是受控细胞生长的一种形式,其中,一种类型的完全分化的细胞取代另一种类型的分化细胞。
[0036]活化的淋巴样细胞的病理学生长常常导致自身免疫性疾病或慢性炎症性病症。当用于本文中时,术语“自身免疫性疾病”指的是其中器官产生可识别器官自身分子、细胞或组织的抗体或免疫细胞的任何病症。自身免疫性疾病的非限制性实例包括自身免疫性溶血性贫血、自身免疫性肝炎、Berger’s病或IgA肾病、口炎性腹泻、慢性疲乏综合征、克罗恩病、皮肌炎、纤维肌痛、移植物抗宿主病、Grave’s病、Hashimoto’s甲状腺炎、自发性血小板减少性紫癜、扁平苔藓、多发性硬化、重症肌无力、银屑病、风湿热、风湿性关节炎、硬皮病、Sjgren′s综合征、系统性红斑狼疮、1型糖尿病、溃疡性结肠炎和白癫风等。
[0037]术语“肿瘤性疾病”当用于本文中时,指的是良性(非癌性)或恶性(癌性)细胞的任何异常生长。
[0038]术语“抗肿瘤剂”当用于本文中时,指的是延迟目标(例如恶性的)赘生物增殖、生长或扩散的任何化合物。
[0039]术语“预防(prevent)”、“预防(preventing)”和“预防(prevention)”当用于本文中时,指的是减少动物病态细胞(例如过度增殖细胞或赘生细胞)出现。预防可以是完全的,例如使患者完全缺乏病态细胞。预防也可以是部分的,例如患者存在的病态细胞比未经本发明处理存在的病态细胞少。
[0040]术语"凋亡调节剂"当用于本文中时,指的是参与调节(例如抑制、减少、增加、促进)凋亡的药剂。凋亡调节剂的实例包括含死亡结构域的蛋白质,例如但不限于,Fas/CD95、TRAMP、TNF RI、DR1、DR2、DR3、DR4、DR5、DR6、FADD和RIP。凋亡调节剂的其它实例包括但不限于TNFα、Fas配体、Fas/CD95和其它TNF家族受体的抗体、TRAIL、TRAILR1或TRAILR2的抗体、Bcl-2、D53、BAX、BAD、Akt、CAD、PI3激酶、PP1和半胱天冬酶蛋白。调节剂在广义上包括TNF家族受体和TNF家族配体的激动剂和拮抗剂。凋亡调节剂可为溶解的或膜结合的(例如配体或受体)。优选的凋亡调节剂是凋亡诱导剂,如TNF或TNF-相关配体,尤其是TRAMP配体,Fas/CD95配体,TNFR-1配体或TRAIL。
[0041]本发明的Stat3活性抑制剂是STA-21或其衍生物、类似物、前药或药学可接受的盐。
[0042]某些本发明化合物可以立体异构体形式存在,包括旋光异构体。本发明包括所有的立体异构体,既包括这些立体异构体的外消旋混合物,又包括单个对映异构体,单个对映异构体可根据本领域技术人员公知的方法分离。
[0043]可用本领域公知的常规方法分离本发明化合物。
[0044]本发明的一个重要方面是STA-21或其衍生物、类似物、前药或药学可接受的盐可以通过引起细胞周期停滞和/或凋亡至少部分地抑制细胞生长,还可以响应凋亡诱导信号加强引起细胞周期停滞和/或凋亡。因此,预期这些化合物可增加细胞对凋亡诱导剂的敏感性,包括对这些诱导剂有抵抗力的细胞。本发明的Stat3活性抑制剂可以用于在任何病症中诱导凋亡,所述病症是可以通过诱导凋亡而治疗、改善或预防的病症。在一个实施方案中,该抑制剂可以用于诱导具有增加的Stat3活性的细胞凋亡。
[0045]在另一个实施方案中,本发明涉及调节凋亡相关状况,该状况与一种或多种凋亡调节剂相关。凋亡调节剂的实例包括但不限于,Fas/CD95、TRAMP、TNF RI、DR1、DR2、DR3、DR4、DR5、DR6、FADD、RIP、TNFα、Fas配体、TRAIL、TRAILR1或TRAILR2抗体、Bcl-2、p53、BAX、BAD、Akt、CAD、PI3激酶、PP1和半胱天冬酶蛋白。参与凋亡的起始、决定和降解阶段的其它试剂也包括在内。凋亡调节剂的实例包括其活性、存在或浓度变化可以调节受试者凋亡的试剂。优选的凋亡调节剂是凋亡诱导剂,如TNF或TNF-相关配体,尤其是TRAMP配体,Fas/CD95配体,TNFR-1配体或TRAIL。
[0046]在一些实施方案中,本发明组合物和方法被用于治疗动物(例如哺乳动物患者,包括但不限于人类和兽医动物)的患病细胞、组织、器官或病症和/或疾病状况。在这方面,各种疾病和病理学可用本发明方法和组合物治疗或预防。这些疾病和病症的非限制性实例列表包括但不限于乳腺癌、前列腺癌、淋巴瘤、皮肤癌、胰腺癌、结肠癌、黑素瘤、恶性黑素瘤、卵巢癌、脑癌、原发性脑癌、头颈癌、神经胶质瘤、成胶质细胞瘤、肝癌、膀胱癌、非小细胞肺癌、头或颈癌、乳腺癌、卵巢癌、肺癌、小细胞肺癌、维尔姆斯肿瘤、宫颈癌、睾丸癌、膀胱癌、胰腺癌、胃癌、结肠癌、前列腺癌、泌尿生殖器癌、甲状腺癌、食管癌、骨髓瘤、多发性骨髓瘤、肾上腺癌、肾细胞癌、子宫内膜癌、肾上腺皮质癌、恶性胰腺胰岛素瘤、恶性类癌性癌、绒毛膜癌、蕈样肉芽肿病、恶性高钙血症、宫颈增生、白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、急性髓细胞性白血病、慢性髓细胞性白血病、慢性粒细胞性白血病、急性粒细胞性白血病、毛细胞性白血病、成神经细胞瘤、横纹肌肉瘤、卡波济肉瘤、真性红细胞增多、原发性血小板增多(essential thrombocytosis)、何杰金病、非何杰金淋巴瘤、软组织肉瘤、骨肉瘤、原发性巨球蛋白血症和视网膜母细胞瘤等,T和B细胞介导的自身免疫性疾病;炎性疾病;感染;过度增殖性疾病;AIDS;变性病症、血管疾病等。在一个实施方案中,癌是乳腺癌或卵巢癌。在一些实施方案中,所治疗的癌细胞是转移的。在其它实施方案中,所治疗的癌细胞对抗癌剂耐药。
[0047]在一些实施方案中,适合用本发明组合物和方法治疗的感染包括但不限于由病毒、细菌、真菌、支原体、和朊病毒等引起的感染。
[0048]本发明的一些实施方案提供了施用有效量的本发明组合物和至少一种另外的治疗剂(包括但不限于化疗抗肿瘤剂、凋亡调节剂、抗菌剂、抗病毒剂、抗真菌剂和抗炎剂)和/或治疗技术(例如外科干预和/或放射疗法)的方法。
[0049]很多合适的抗癌剂都可用于本发明的方法。事实上,本发明关注于,但不限于很多抗癌剂的给药,例如:诱导凋亡的药剂;多核苷酸(例如反义核苷酸、核酶、siRNA);多肽(例如酶和抗体);生物模拟物(例如棉酚或BH3模拟物);与Bcl-2家族蛋白如Bax结合的试剂(例如寡聚体或复合物);生物碱类;烷化剂;抗肿瘤抗生素;抗代谢物;激素类;铂类化合物;单克隆或多克隆抗体(例如抗癌药、毒素、防御素结合的抗体),毒素;放射性核素;生物效应调节剂(例如干扰素类(例如IFN-α)和白介素类(例如IL-2));过继免疫治疗剂;造血生长因子;诱导肿瘤细胞分化的药剂(例如全反式维甲酸);基因治疗剂(例如反义治疗剂和核苷酸);肿瘤疫苗;血管生成抑制剂;蛋白体抑制剂;NF-KB调节剂;抗-CDK化合物;和HDAC抑制剂等。适合于与公开的化合物一起给药的化疗化合物和抗癌疗法的很多其它实例是本领域技术人员已知的。
[0050]在优选的实施方案中,抗癌剂包括诱导或刺激凋亡的试剂。诱导凋亡的试剂包括但不限于放射线(例如X-射线、γ射线、UV);肿瘤坏死因子(TNF)-相关因子(例如TNF家族受体蛋白、TNF家族配体、TRAIL、对TRAILR1或TRAILR2的抗体);激酶抑制剂(例如表皮生长因子受体(EGFR)激酶抑制剂、血管生长因子受体(VGFR)激酶抑制剂、成纤维细胞生长因子受体(FGFR)激酶抑制剂、血小板衍生的生长因子受体(PDGFR)激酶抑制剂和Bcr-Abl激酶抑制剂(如GLEEVEC));反义分子;抗体(例如赫赛汀、B细胞单克隆抗体、ZEVALIN和AVASTIN);抗雌激素类(例如雷洛昔芬和他莫昔芬);抗雄激素类(例如氟他胺、比卡鲁胺、非那雄胺、氨鲁米特、酮康唑和皮质激素类);环氧化酶2(COX-2)抑制剂(例如塞来考昔、美洛昔康、NS-398和非甾体抗炎药(NSAIDs));抗炎药(例如保泰松、地卡特隆、去氢可的松、地塞米松、氟甲去氢氢化可的松、intensol、地塞米松磷酸钠、甲氟烯索、羟氯喹、泼尼松、氟美松、泼尼松制剂、羟布宗、泼尼松磷酸钠制剂、保泰松、硫酸羟氯喹、泼尼松龙、泼尼松、PRELONE和坦特利尔);和癌症化学治疗药(例如伊立替康(CAMPTOSAR)、CPT-11、氟达拉滨(FLUDARA)、达卡巴嗪(DTIC)、地塞米松、米托蒽醌、MYLOTARG、VP-16、顺铂、卡铂、奥沙利铂、5-FU、多柔比星、吉西他滨、bortezomib、gefitinib、贝伐单抗、泰索帝或泰素);细胞信号分子;神经酰胺和细胞因子;和十字孢碱等。
[0051]在另外的实施方案中,本发明的组合物和方法提供了式I化合物和至少一种抗增殖剂或抗肿瘤剂,其选自烷化剂、抗代谢物和天然产物(例如草药和其它植物和/或动物来源的化合物)。
[0052]适用于本发明组合物和方法的烷化剂包括但不限于:1)氮芥类(例如氮芥、环磷酰胺、异环磷酰胺、美法仑(L-沙可来新);和苯丁酸氮芥);2)氮丙啶和甲基密胺(例如六甲蜜胺和塞替派);3)磺酸烷基酯(alkyl sulfonates)(例如白消安);4)亚硝基脲类(例如卡莫司汀(BCNU);洛莫司汀(CCNU);司莫司汀(甲基-CCNU);和链佐星(链脲霉素));和5)三氮烯类(例如达卡巴嗪(DTIC;二甲基三氮烯基咪唑甲酰胺(dimethyltriazenoimid-azolecarboxamide))。
[0053]在一些实施方案中,适用于本发明组合物和方法的抗代谢物包括但不限于:1)叶酸类似物(例如甲氨蝶呤(氨甲蝶呤));2)嘧啶类似物(例如氟尿嘧啶(5-氟尿嘧啶;5-FU)、氟尿苷(氟尿嘧啶脱氧核苷;FudR)和阿糖胞苷(阿糖胞苷));和3)嘌呤类似物(例如巯嘌呤(6-巯嘌呤;6-MP)、硫鸟嘌呤(6-硫鸟嘌呤;TG)和喷司他丁(2’-脱氧柯福霉素))。
[0054]在更进一步的实施方案中,适用于本发明组合物和方法的化疗剂包括但不限于:1)长春花碱类(例如长春碱(VLB)、长春新碱);2)鬼臼乙叉甙类(例如依托泊苷和替尼泊苷);3)抗生素(例如放线菌素(放线菌素D)、柔红霉素(柔红霉素;红比霉素)、多柔比星、博来霉素、普卡霉素(光辉霉素)和丝裂霉素(丝裂霉素C));4)酶类(例如L-门冬酰胺酶);5)生物效应调节剂(例如干扰素-α);6)铂配位络合物(例如顺铂(顺-DDP)和卡铂);7)蒽二酮类(例如米托蒽醌);8)取代的脲类(例如羟基脲);9)甲肼衍生物(例如丙卡巴肼(N-甲肼;MIH));10)肾上腺皮质抑制剂(例如米托坦(o,p’-DDD)和氨鲁米特);11)肾上腺皮质类固醇类(例如泼尼松);12)黄体酮(例如己酸羟孕酮、醋酸甲羟孕酮和醋酸甲地孕酮);13)雌激素(例如己烯雌酚和乙炔雌二醇);14)抗雌激素药(例如他莫昔芬);15)雄激素类(例如丙酸睾丸酮和氟甲睾酮);16)抗雄激素类(例如氟他胺);和17)促性腺激素释放激素类似物(例如醋酸亮丙瑞林)。
[0055]常规用于癌症治疗的任何溶瘤细胞剂都可在本发明组合物和方法中发挥作用。例如,美国食品与药品管理局维持了批准用于美国的溶瘤细胞剂的处方集。U.S.F.D.A.的国际对应机构(International counterpart agencies)维持了类似的处方集。表1提供了批准用于美国的示例性抗肿瘤剂的列表。本领域技术人员将会认识到在所有美国批准的化疗剂上都必需具备的“产品标签”描述了示例性药剂的批准适应症、给药信息和毒性数据等。
表1.
阿地白介素(脱-丙氨酰-1,丝氨酸-125人白介素-2) | Proleukin | Chiron Corp.,Emeryville,CA |
阿仑单抗(IgG1κ抗CD52抗体) | Campath | Millennium and ILEXPartners,LP,Cambridge,MA |
阿利维A酸(9-顺式维甲酸) | Panretin | LigandPharmaceuticals,Inc.,San Diego CA |
别嘌醇(1,5-二氢-4H-吡唑[3,4-d]嘧啶-4-酮单钠盐) | Zyloprim | GlaxoSmithKline,Research TrianglePark,NC |
六甲蜜胺(N,N,N′,N′,N",N",-六甲基-1,3,5-三嗪-2,4,6-三胺) | Hexalen | US Bioscience,WestConshohocken,PA |
氨磷汀(乙硫醇,2-[(3-氨基丙基)氨基]-,二氢磷酸盐(酯)) | Ethyol | US Bioscience |
阿那曲唑(1,3-苯双乙腈,a,a,a′,a′-四甲基-5-(1H-1,2,4-三唑-1-基甲基)) | Arimidex | AstraZenecaPharmaceuticals,LP,Wilmington,DE |
三氧化二砷 | Trisenox | Cell Therapeutic,Inc.,Seattle,WA |
门冬酰胺酶(L-天冬酰胺酰胺基水解酶,EC-2型) | Elspar | Merck & Co.,Inc.,Whitehouse Station,NJ |
BCGLive(牛分枝杆菌(Bacillus Calmette-Gukin[BCG],次代株Montreal)减毒菌株的冻干制剂) | TICE BCG | Organon Teknika,Corp.,Durham,NC |
贝沙罗汀胶囊(4-[1-(5,6,7,8-四氢-3,5,5,8,8-五甲基-2-萘基)乙烯基]苯甲酸) | Targretin | LigandPharmaceuticals |
贝沙罗汀凝胶 | Targretin | LigandPharmaceuticals |
博来霉素(轮丝链霉菌产生的细胞毒素糖肽类抗生素;博来霉素A2和博来霉素B2) | Blenoxane | Bristol-Myers SquibbCo.,NY,NY |
卡培他滨(5′-去氧-5-氟-N-[(戊氧基)羰基]-胞啶) | Xeloda | Roche |
卡铂(铂,二胺[1,1-环丁烷二羧酸合(2-)-0,0′]-,(SP-4-2)) | Paraplatin | Bristol-Myers Squibb |
卡莫司汀(1,3-双(2-氯乙基)-1-亚硝基脲) | BCNU,BiCNU | Bristol-Myers Squibb |
卡莫司汀与聚苯丙生20植入剂 | GliadelWafer | GuilfordPharmaceuticals,Inc.,Baltimore,MD |
塞来考昔(作为4-[5-(4-甲苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺) | Celebrex | SearlePharmaceuticals,England |
苯丁酸氮芥(4-[双(2-氯乙基)氨基]苯丁酸) | Leukeran | GlaxoSmithKline |
顺铂(PtCl2H6N2) | Platinol | Bristol-Myers Squibb |
克拉屈滨(2-氯-2′-去氧-b-D-阿糖腺苷) | Leustatin,2-CdA | R.W.JohnsonPharmaceuticalResearch Institute,Raritan,NJ |
环磷酰胺(2-[双(2-氯乙基)氨基]四氢-2H-13,2-氧氮杂膦2-氧化物一水合物) | Cytoxan,Neosar | Bristol-Myers Squibb |
阿糖胞苷(1-b-D-阿糖呋喃糖胞噻啶,C9H13N3O5) | Cytosar-U | Pharmacia & UpjohnCompany |
阿糖胞苷脂质体 | DepoCyt | Skye Pharmaceuticals,Inc.,San Diego,CA |
达卡巴嗪(5-(3,3-二甲基-1-三氮烯基)-咪唑基-4-甲酰胺(DTIC)) | DTIC-Dome | Bayer AG,Leverkusen,Germany |
放线菌素,放线菌素D(由Streptomyces parvullus产生的放线菌素,C62H86N12O16) | Cosmegen | Merck |
Darbepoetin alfa(重组肽) | Aranesp | Amgen,Inc.,ThousandOaks,CA |
柔红霉素脂质体((8S-顺式)-8-乙酰基-10-[(3-氨基-2,3,6-三脱氧-α-L-来苏-己吡喃糖基)氧代]-7,8,9,10-四氢-6,8,11-三羟基-1-甲氧基-5,12-并四苯二酮盐酸盐) | DanuoXome | NexstarPharmaceuticals,Inc.,Boulder,CO |
柔红霉素HCl,柔红霉素((1S,3S)-3-乙酰基-1,2,3,4,6,11-六氢-3,5,12-三羟基-10-甲氧基-6,11-二氧代-1-并四苯基3-氨基-2,3,6-三脱氧-(α)-L-来苏-己吡喃糖盐酸盐) | Cerubidine | Wyeth Ayerst,Madison,NJ |
地尼白介素-毒素连接物(重组肽) | Ontak | Seragen,Inc.,Hopkinton,MA |
右雷佐生((S)-4,4′-(1-甲基-1,2-乙二基)双-2,6-哌嗪二酮) | Zinecard | Pharmacia & UpjohnCompany |
多西紫杉醇((2R,3S)-N-羧基-3-苯基异丝氨酸,N-叔丁酯,13-酯,与5b-20-环氧-12a,4,7b,10b,13a-六羟基紫杉-11-烯-9-酮4-醋酸酯2-苯甲酸酯,三水合物) | Taxotere | AventisPharmaceuticals,Inc.,Bridgewater,NJ |
多柔比星HCl(8S,10S)-10-[(3-氨基-2,3,6-三脱氧-a-L-来苏-己吡喃基)氧代]-8-羟乙酰基-7,8,9,10-四氢-6,8,11-三羟基-1-甲氧基-5,12-并四苯二酮盐酸盐) | Adriamycin,Rubex | Pharmacia & UpjohnCompany |
多柔比星 | Adriamycin PFSIntraveno | Pharmacia & UpjohnCompany |
usinjection | ||
多柔比星脂质体 | Doxil | SequusPharmaceuticals,Inc.,Menlo park,CA |
丙酸屈他雄酮(17b-羟基-2a-甲基-5a-雄甾烷-3-酮丙酸盐) | Dromostanolone | Eli Lilly & Company,Indianapolis,IN |
丙酸屈他雄酮 | Masteroneinjection | Syntex,Corp.,PaloAlto,CA |
Elliott′s B溶液 | Elliott′sBSolution | Orphan Medical,Inc |
表柔比星((8S-顺式)-10-[(3-氨基-2,3,6-三脱氧-a-L-阿拉伯糖-己吡喃基)氧代]-7,8,9,10-四氢-6,8,11-三羟基-8-(羟基乙酰基)-1-甲氧基-5,12-并四苯二酮盐酸盐) | Ellence | Pharmacia & UpjohnCompany |
阿法依伯汀(重组肽) | Epogen | Amgen,Inc |
雌莫司汀(雌-1,3,5(10)-三烯-3,17-二醇(17(β))-,3-[双(2-氯乙基)氨基甲酸酯]17-(二氢磷酸酯),二钠盐,一水合物,或雌二醇3-[双(2-氯乙基)氨基甲酸酯]17-(二氢磷酸酯),二钠盐,一水合物) | Emcyt | Pharmacia & UpjohnCompany |
磷酸依托泊苷(4′-去甲基表鬼臼毒素9-[4,6-O-(R)-亚乙基-(β)-D-吡喃葡萄糖苷],4′-(二氢磷酸酯)) | Etopophos | Bristol-Myers Squibb |
依托泊苷,VP-16(4′-去甲基表鬼臼毒素9-[4,6-0-(R)-亚乙基-(β)-D-吡喃葡萄糖苷]) | Vepesid | Bristol-Myers Squibb |
依西美坦(6-亚甲基雄-1,4-二烯-3,17-二酮) | Aromasin | Pharmacia & UpjohnCompany |
非格司亭(r-metHuG-CSF) | Neupogen | Amgen,Inc |
氟尿苷(动脉内)(2′-去氧-5-氟尿苷) | FUDR | Roche |
氟达拉滨(抗病毒剂阿糖腺苷,9-b-D-阿糖呋喃糖腺嘌呤(ara-A)的氟化核苷酸类似物) | Fludara | Berlex Laboratories,Inc.,Cedar Knolls,NJ |
氟尿嘧啶,5-FU(5-氟-2,4(1H,3H)-嘧啶二酮) | Adrucil | ICN Pharmaceuticals,Inc.,Humacao,PuertoRico |
氟维司群(7-α-[9-(4,4,5,5,5-五氟戊基亚磺酰基)壬基]雌-1,3,5-(10)-三烯-3,17-β-二醇) | Faslodex | IPR Pharmaceuticals,Guayama,Puerto Rico |
吉西他滨(2′-去氧-2′,2′-二氟胞苷单盐酸盐(b-异构体)) | Gemzar | Eli Lilly |
吉姆单抗奥佐米星(抗-CD33 hP67.6) | Mylotarg | Wyeth Ayerst |
醋酸戈舍瑞林([D-Ser(But)6,Azgly10]LHRH的醋酸盐;pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2醋酸盐[C59H84N18O14·(C2H4O2)x | ZoladexImplant | AstraZenecaPharmaceuticals |
羟基脲 | Hydrea | Bristol-Myers Squibb |
替伊莫单抗(由单克隆抗体Ibritumomab和联结子-螯合剂tiuxetan[N-[2-二(羧基甲基)氨基]-3-(对-异氰硫基苯基)-丙基]-[N-[2-二(羧基甲基)氨基]-2-(甲基)-乙基]甘氨酸之间的硫脲共价键产生的免疫轭合物) | Zevalin | Biogen IDEC,Inc.,Cambridge MA |
伊达比星(5,12-并四苯二酮,9-乙酰基-7-[(3-氨基-2,3,6-三脱氧-(α)-L-来苏-己吡喃糖基)氧基]-7,8,9,10-四氢-6,9,11-三羟基盐酸盐,(7S-顺式)) | Idamycin | Pharmacia & UpjohnCompany |
异环磷酰胺(3-(2-氯乙基)-2-[(2-氯乙基)氨基]四氢-2H-1,3,2-氧氮杂膦2-氧化物) | IFEX | Bristol-Myers Squibb |
甲磺酸伊马替尼(Imatinib Mesilate)(4-[(4-甲基-1-哌嗪基)甲基]-N-[4-甲基 | Gleevec | Novartis AG,Basel,Switzerland |
-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]-苯基]苯甲酰胺甲磺酸盐) | ||
干扰素α-2a(重组肽) | Roferon-A | Hoffmann-La Roche,Inc.,Nutley,NJ |
干扰素α-2b(重组肽) | Intron A(LyophilizedBetaseron) | Schering AG,Berlin,Germany |
伊立替康HCl((4S)-4,11-二乙基-4-羟基-9-[(4-哌啶子基哌啶子基)羰氧基]-1H-吡喃并[3’,4’:6,7]吲嗪并[1,2-b]喹啉-3,14(4H,12H)二酮盐酸盐三水合物) | Camptosar | Pharmacia & UpjohnCompany |
来曲唑(4,4’-(1H-1,2,4-三唑-1-基亚甲基)二苄腈) | Femara | Novartis |
亚叶酸钙(L-谷氨酸,N[4[[(2氨基-5-甲酰基-1,4,5,6,7,8六氢4氧代6-蝶啶基)甲基]氨基]苯甲酰基],钙盐(1:1)) | Wellcovorin,Leucovorin | Immunex,Corp.,Seattle,WA |
左旋咪唑HCl((-)-(S)-2,3,5,6-四氢-6-苯基咪唑并[2,1-b]噻唑单盐酸盐C11H12N2S·HCl) | Ergamisol | Janssen ResearchFoundation,Titusville,NJ |
罗莫司汀(1-(2-氯-乙基)-3-环己基-1-亚硝基脲) | CeeNU | Bristol-Myers Squibb |
Meclorethamine,氮芥(2-氯-N-(2-氯乙基)-N-甲基乙胺盐酸盐) | Mustargen | Merck |
醋酸甲地孕酮17α(乙酰氧基)-6-甲基孕-4,6-二烯-3,20-二酮 | Megace | Bristol-Myers Squibb |
美法仑,L-PAM(4-[二(2-氯乙基)氨基]-L-苯丙氨酸) | Alkeran | GlaxoSmithKline |
巯基嘌呤,6-MP(1,7-二氢-6H-嘌呤-6-硫酮单水合物) | Purinethol | GlaxoSmithKline |
美司钠(2-巯基乙烷磺酸钠) | Mesnex | Asta Medica |
甲氨蝶呤(N-[4-[[(2,4-二氨基-6-蝶啶基)甲基]甲基氨基]苯甲酰基]-L-谷氨酸) | Methotrexate | Lederle Laboratories |
甲氧沙林(9-甲氧基-7H-furo[3,2-g][1]-苯并呋喃-7-酮) | Uvadex | Therakos,Inc.,WayExton,Pa |
丝裂霉素C | Mutamycin | Bristol-Myers Squibb |
丝裂霉素C | Mitozytrex | SuperGen,Inc.,Dublin,CA |
米托坦(1,1-二氯-2-(邻-氯苯基)-2-(对-氯苯基)乙烷) | Lysodren | Bristol-Myers Squibb |
米托蒽醌(1,4-二羟基-5,8-二[2-[(2-羟基乙基)氨基]乙基]氨基)-9,10-蒽二酮二盐酸盐) | Novantrone | Immunex Corporation |
苯丙酸诺龙 | Durabolin-50 | Organon,Inc.,WestOrange,NJ |
诺非单抗 | Verluma | Boehringer IngelheimPharma KG,Germany |
奥普瑞白介素(IL-11) | Neumega | Genetics Institute,Inc.,Alexandria,VA |
奥沙利铂(顺式-[(1R,2R)-1,2-环己烷二胺-N,N’][oxalato(2-)-0,0’]铂) | Eloxatin | Sanofi Synthelabo,Inc.,NY,NY |
紫杉醇(具有(2R,3S)-N-苯甲酰基-3-苯基异丝氨酸的5β,20-环氧-1,2a,4,7β,10β,13a-六羟基紫杉-11-烯-9-酮4,10-二醋酸2-苯甲酸13-酯) | TAXOL | Bristol-Myers Squibb |
氨羟二膦酸二钠(膦酸(3-氨基-1-羟基亚丙基)二-,二钠盐,五水合物,(APD)) | Aredia | Novartis |
培加酶((单甲氧基聚乙二醇琥珀酰亚氨基)11-17-腺苷脱氨基酶) | Adagen(PegademaseBovine) | EnzonPharmaceuticals,Inc.,Bridgewater,NJ |
培加帕酶 | Oncaspar | Enzon |
(单甲氧基聚乙二醇琥珀酰亚氨基L-天门冬酰胺酶) | ||
聚乙二醇非格司亭(重组甲硫氨酰基人G-CSF(非格司亭)和单甲氧基聚乙二醇的共价轭合物) | Neulasta | Amgen,Inc |
喷司他丁 | Nipent | Parke-DavisPharmaceuticalCo.,Rockville,MD |
哌泊溴烷 | Vercyte | Abbott Laboratories,Abbott Park,IL |
普卡霉素,光辉霉素(由Sreptomyces plicatus产生的抗生素) | Mithracin | Pfizer,Inc.,NY,NY |
卟吩姆钠 | Photofrin | QLTPhototherapeutics,Inc.,Vancouver,Canada |
丙卡巴肼(N-异丙基-μ-(2-甲基肼基)-对-甲苯酰胺单盐酸盐) | Matulane | Sigma TauPharmaceuticals,Inc.,Gaithersburg,MD |
奎纳克林(6-氯-9-(1-甲基-4-二乙基-胺)丁基氨基-2-甲氧基吖啶) | Atabrine | Abbott Labs |
拉布立酶(重组肽) | Elitek | Sanofi-Synthelabo,Inc., |
利妥昔单抗(重组抗-CD20抗体) | Rituxan | Genentech,Inc.,SouthSan Francisco,CA |
沙格司亭(重组肽) | Prokine | Immunex Corp |
链佐星(链佐星2-脱氧-2-[[(甲基亚硝基氨基)羰基]氨基]-a(和b)-D-吡喃葡萄糖和220mg无水柠檬酸 | Zanosar | Pharmacia & UpjohnCompany |
滑石粉(MgSi4O10(OH)2) | Sclerosol | Bryan,Corp.,Woburn,MA |
他莫昔芬((Z)2-[4-(1,2-二苯基-1-丁烯基)苯氧基]-N,N-二甲基乙胺2-羟基-1,2,3-丙烷三羧酸盐(1:1)) | Nolvadex | AstraZenecaPharmaceuticals |
替莫唑胺(3,4-二氢-3-甲基-4-氧代咪唑并[5,1-d]-as-四嗪-8-甲酰胺) | Temodar | Schering |
替尼泊苷,VM-26(4’-脱甲基鬼臼乙叉碱9-[4,6-0-(R)-2-噻吩亚甲基-(β)-D-吡喃葡萄糖苷]) | Vumon | Bristol-Myers Squibb |
睾内酯(13-羟基-3-氧代-13,17-开环雄甾-1,4-二烯-17-酸[dgr]-内酯) | Teslac | Bristol-Myers Squibb |
硫鸟嘌呤,6-TG(2-氨基-1,7-二氢-6H-嘌呤-6-硫酮) | Thioguanine | GlaxoSmithKline |
噻替派(环乙亚胺,1,1’,1”-膦基thioylidynetris-,或三(1-环乙亚胺基)膦硫化物) | Thioplex | Immunex Corporation |
托泊替康HCl((S)-10-[(二甲基氨基)甲基]-4-乙基-4,9-二羟基-1H-吡喃并[3’,4’:6,7]吲嗪并[1,2-b]喹啉-3,14-(4H,12H)-二酮单盐酸盐) | Hycamtin | GlaxoSmithKline |
托瑞米芬(2-(对-[(Z)-4-氯-1,2-二苯基-1-丁烯基]-苯氧基)-N,N-二甲基乙基胺柠檬酸盐(1:1)) | Fareston | RobertsPharmaceutical Corp.,Eatontown,NJ |
脱西莫单抗,I131脱西莫单抗(重组的鼠科动物免疫治疗的单克隆IgG2aλ抗-CD20抗体(I131是一种放射免疫治疗抗体)) | Bexxar | Corixa Corp.,Seattle,WA |
曲妥单抗(重组的单克隆IgG1κ抗HER2抗体) | Herceptin | Genentech,Inc |
维甲酸,ATRA(全反式视黄酸) | Vesanoid | Roche |
尿嘧啶氮芥 | UracilMustardCapsules | Roberts Labs |
戊柔比星,N-三氟乙酰基阿霉素-14-戊酸盐((2S-顺式)-2-[1,2,3,4.6,11]-六氢-2,5,12-三羟基-7-甲氧基-6,11-二氧代-[[42,3,6-三脱氧-3-[(三氟乙酰基)-氨 | Valstar | Anthra-->Medeva |
基-α-L-来苏-己糖吡喃糖基]氧基]-2-并四苯基]-2-氧代乙基戊酸盐) | ||
长春碱,长春新碱(C46H56N4O10 H2SO4) | Velban | Eli Lilly |
长春新碱(C46H56N4O10 H2SO4) | Oncovin | Eli Lilly |
长春瑞滨(3’,4’-二脱氢-4’-脱氧-C’-去甲长春碱[R-(R*,R*)-2,3-二羟基丁二酸盐(1:2)] | Navelbine | GlaxoSmithKline |
唑来膦酸盐,唑来膦酸((1-羟基-2-咪唑-1-基-膦酰基乙基)膦酸单水合物) | Zometa | Novartis |
[0056]为了更加详细地说明抗癌剂和其它治疗剂,本领域技术人员可参考任何有益的手册,包括但不限于the Physician′s DeskReference和Goodman and Gilman′s"Pharmaceutical Basis ofTherapeutics"第十版,Hardman等编辑,2002。
[0057]本发明提供了与放射疗法一起施用本发明化合物的方法。本发明不受用于向动物递送治疗剂量的放射线的类型、量、或递送和给药系统的限制。例如,动物可接受光子放疗、粒子束放疗、其它类型的放疗、及其联合。在一些实施方案中,用线性加速器向动物递送放射线。在又一个实施方案中,用γ刀递送放射线。
[0058]放射源可以从外部或内部递送给动物。外部射线疗法是最常用的,包括通过例如线性加速器将一束高能量辐射通过皮肤指向肿瘤部位。虽然辐射光束集中在肿瘤部位,但是,其几乎不能避免接触正常的健康组织。但是,外部辐射通常可以被患者良好的耐受。内部辐射治疗涉及将一种辐射发射源,如小珠、导线、小丸、胶囊、微粒等植入到机体内的肿瘤部位或肿瘤附近,包括使用特异性靶向于癌细胞的传递系统(例如,使用与癌细胞结合配体相连的微粒)。在治疗后可以取出该类植入物,或者可以将其无活性地留在机体中。内部辐射治疗的类型非限制性地包括近程放射治疗、间质内照射、腔内辐射、放射免疫疗法等。
[0059]所述动物可以任选地接受放射致敏剂(例如甲硝唑、米索硝唑、动脉内Budr、静脉内碘脱氧嘧啶核苷(IudR)、硝基咪唑、5-取代的-4-硝基咪唑类、2H-异吲哚二酮、[[(2-溴乙基)-氨基]甲基]-硝基-1H-咪唑-1-乙醇、硝基苯胺衍生物、DNA-affinic低氧选择性细胞毒素、卤化DNA配体、1,2,4苯并三嗪氧化物、2-硝基咪唑衍生物、包含氟的硝基吡咯衍生物、苯甲酰胺、烟酰胺、吖啶-插入剂、5-硫代四唑(thiotretrazole)衍生物、3-硝基-1,2,4-三唑、4,5-二硝基咪唑衍生物、羟基化texaphrins、顺铂、丝裂霉素、替拉扎明(tiripazamine)、亚硝基脲、巯基嘌呤、甲氨蝶呤、氟尿嘧啶、博来霉素、长春新碱、卡铂、表柔比星、多柔比星、环磷酰胺、长春地辛、依托泊苷、紫杉醇、热(过热)等)、辐射防护剂(例如巯乙胺、氨基烷基二氢硫代磷酸酯、阿米斯丁(WR 2721)、IL-I、IL-6等)。放射致敏剂增强了肿瘤细胞的杀灭。放射防护剂包括健康组织不受辐射有害作用的影响。
[0060]可以给患者使用任何类型的辐射,只要辐射剂量可以被患者耐受并且不产生不可接受的消极副作用即可。适宜的放疗类项目包括例如电离(电磁)放疗(例如,X-射线或γ射线)或粒子束辐射治疗(例如高线性能量辐射(high linear energy radiation))。电离辐射被定义为包含具有足以产生电离(即获得或损失电子)的能量的微粒或光子的辐射(如例如US 5,770,581中所述,其本文被全部引入作为参考)。临床医师可以至少部分控制辐射的作用。为了获得最大靶细胞接触和降低毒性,优选地对辐射的剂量进行分级给药。
[0061]被给药于动物的辐射的总剂量优选地为约0.01戈瑞(Gy)至约100Gy。在治疗过程中,更优选地使用约10Gy至约65Gy(例如,约15Gy、20Gy、25Gy、30Gy、35Gy、40Gy、45Gy、50Gy、55Gy、或60Gy)。虽然在一些实施方案中,可以在一天过程中给予辐射的全部剂量,但是理想地将该总剂量分成几部分并将其在几天内进行给药。令人希望地是在至少约3天,例如,至少5、7、10、14、17、21、25、28、32、35、38、42、46、52、或56天(约1-8周)的过程中进行放疗。因此,辐射的日剂量将包含约1-5Gy(例如,约1Gy、1.5Gy、1.8Gy、2Gy、2.5Gy、2.8Gy、3Gy、3.2Gy、3.5Gy、3.8Gy、4Gy、4.2Gy、或4.5Gy),优选1-2Gy(例如,1.5-2Gy)。所述辐射的日剂量应足以诱导所靶向细胞的破坏。如果在一定时期内扩张(stretched),则优选地不每天进行辐射,从而使得动物可以进行休息和实现该治疗的作用。例如,对于各治疗周而言,理想地连续5天进行辐射,然后两天不进行治疗,从而使得每周休息2天。但是,根据动物的响应和任何可能的副作用,辐射可以被1天/周、2天/周、3天/周、4天/周、5天/周、6天/周地进行或者一周7天都进行。可以在治疗周期的任何时间开始辐射治疗。优选地在第1或2周开始辐射,并且在该治疗周期的其余持续时间内进行辐射。例如,在包含对例如实体瘤治疗6周的治疗时期内,在该时期的1-6周或2-6周内进行辐射。或者,在包含5周的治疗时期的1-5周或2-5周内进行辐射。但是,并不是要用这些实例性放疗给药时间表对本发明进行限制。
[0062]还可以用抗微生物的治疗剂作为本发明的治疗剂。可以使用可以杀死、抑制或者减弱微生物功能的任何物质以及认为具有该类活性的任何物质。抗微生物剂非限制性地包括单独或联合使用的天然和合成抗生素、抗体、抑制性蛋白(例如防御素)、反义核酸、破裂剂等。实际上,可以使用任何类型的抗生素,非限制性地包括抗菌剂、抗细菌剂、抗病毒剂、抗真菌剂等。
[0063]在本发明的实施方案中,STA-21或其衍生物、类似物、前药或药学可接受的盐和一种或多种治疗剂或抗癌剂在下述一个或多个条件下施用于动物:不同的周期性、不同的持续时间、不同的浓度、不同的给药途径等。在一些实施方案中,化合物在治疗剂或抗癌剂之前施用,如施用治疗剂或抗癌剂之前0.5、1、2、3、4、5、10、12或18小时,1、2、3、4、5或6天,或1、2、3或4周。在一些实施方案中,化合物在治疗剂或抗癌剂之后前施用,如施用抗癌剂之后0.5、1、2、3、4、5、10、12或18小时,1、2、3、4、5或6天,或1、2、3或4周。在一些实施方案中,化合物和治疗剂或抗癌剂同时施用,但给药方案不同,例如,化合物每日施用,而治疗剂或抗癌剂每周、每两周、每三周或每四周施用1次。在其它实施方案中,化合物每周施用1次,而治疗剂或抗癌剂每日、每周、每两周、每三周或每四周施用1次。
[0064]包含在本发明范围之内的组合物包括所有的组合物,这些组合物包含有效实现其预期目的的量的本发明化合物。虽然个体需求不同,但是本领域技术人员可以确定各组分有效量的最佳范围。典型地,化合物可口服施用于哺乳动物,如人类,以0.0025到50mg/kg剂量,或药学可接受盐的相当的量,每天,被治疗响应诱导凋亡病症的动物的体重。优选地,口服施用约0.01到约10mg/kg来治疗、改善或预防这些病症。对于肌内注射来说,剂量通常约为口服剂量一半。例如,适宜的肌内剂量是约0.0025到约25mg/kg,最优选地,是约0.01到约5mg/kg。
[0065]单位口服剂量可包含约0.01到约1000mg,优选约0.1到约100mg的化合物。单位剂量可作为一个或多个片剂或胶囊每日施用1次或多次,每个片剂或胶囊包含约0.1到约10mg,方便地约0.25到50mg的化合物或其溶剂化物。
[0066]在局部用制剂中,化合物的浓度可为约0.01到100mg每克载体。在优选的实施方案中,化合物的浓度为约0.07-1.0mg/ml,更有选地,约0.1-0.5mg/ml,最优选地,约0.4mg/ml。
[0067]除了作为未加工化学品施用化合物外,本发明化合物可以作为包含适宜药学可接受载体的药物制剂的一部分而施用,药学可接受的载体包括赋形剂和辅剂,它们使得从化合物到药学上可以使用的制剂的处理变得容易。优选地,这些制剂,特别是可以口服或局部施用和可以用作优选给药类型的那些制剂,例如片剂、糖衣片、缓释锭剂和胶囊、口腔清洗剂和口腔洗剂、凝胶剂、液体混悬剂、洗发剂、发胶、洗发香波和可以直肠施用的制剂,如栓剂,和通过注射施用的适宜液体,局部或口服,包含约0.01到99%,优选约0.25到75%的活性化合物,和赋形剂。
[0068]本发明的药物组合物可施用于可感受本发明化合物有益效果的任何动物。尽管本发明不打算被限制成这样,但这些动物中最重要的是哺乳动物,如人。其它动物包括牲畜动物(奶牛、绵羊、猪、马、狗、猫等)。
[0069]化合物和其药物组合物可通过实现其预期目的的任何方式施用。例如,可通过胃肠外、皮下、静脉内、肌内、腹膜内、经皮、面颊、鞘内、颅内、鼻内或局部途径施用。任选地,或同时,可通过口服途径施用。施用的剂量取决于受试者的年龄、健康状态和体重,同时治疗的种类,如果还有的话,治疗的频率和所需要效果的性质。
[0070]本发明的药物制剂都以本身已知的方式制备,例如,通过常规的混合、制粒、包糖衣、溶解或冻干方法制备。因此,口服使用的药物制剂可以通过将活性化合物与固体赋形剂混合,任选地研磨所得混合物和处理颗粒混合物,加入适宜的辅剂之后,如果希望或需要,获得片剂或糖衣片核心而获得。
[0071]特别地,适宜的赋形剂是填充剂如糖类,例如乳糖或蔗糖,甘露醇或山梨醇,纤维素制品和/或磷酸钙,例如磷酸三钙或磷酸氢钙,和粘合剂如淀粉糊,使用,例如,玉米淀粉、小麦淀粉、米淀粉、马铃薯淀粉、明胶、黄芪胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮。如果期望,可加入崩解剂,如前述的淀粉和羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂或海藻酸或其盐,如海藻酸钠。辅剂为,尤其是,流动调节剂和润滑剂,例如硅石、滑石、硬脂酸或其盐,如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。如果希望,为糖衣片核心提供了抵抗胃液的适宜的包衣。为此目的,可使用浓缩的糖溶液,糖溶液可任选地包含阿拉伯胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、硝基漆溶液和适宜的有机溶剂或溶剂混合物。为了制备抵抗胃液的包衣,使用了适宜纤维素制品如邻苯二甲酸乙酰纤维素或羟丙基甲基纤维素邻苯二甲酸酯的溶液。染色原料或色素可加入到片剂或糖衣片包衣中,例如,为了鉴定或为了表征活性化合物剂量的组合。
[0072]可以用于口服的其它药物制剂包括由明胶制备的推入配合的胶囊,和由明胶和诸如甘油或山梨醇制备的软的、密封胶囊。推入配合的胶囊可以包含颗粒形式的活性化合物,这些化合物可与填充剂如乳糖,粘合剂如淀粉,和/或润滑剂如滑石或硬脂酸镁和,任选地稳定剂混合。在软胶囊中,活性化合物优选溶解或混悬于适宜的液体当中,例如脂肪油,或液体石蜡。此外,可加入稳定剂。
[0073]可以直肠使用的可能的药物制剂包括,例如,栓剂,其由一种或多种活性化合物与栓剂基质联合组成。适宜的栓剂基质是,例如天然或合成的甘油三酯或链烷烃。另外,还可能使用明胶直肠胶囊,其包括活性化合物和基质的联合。可能的基质材料包括,例如液体甘油三酯、聚乙二醇或链烷烃。
[0074]用于胃肠外给药的适宜制剂包括水溶性形式的活性化合物,例如水溶性盐形式的化合物的水溶液和碱性溶液。此外,还可以使用适宜的油性注射混悬液的形式的活性化合物的混悬液。适宜的亲脂性溶剂或基质包括脂肪油,例如芝麻油、或合成的脂肪酸酯类,例如油酸乙酯或甘油三酯类或聚乙二醇-400。含水注射混悬液可以包含增加该混悬液粘度的物质,所述物质包括例如羧甲基纤维素钠、山梨醇、和/或葡聚糖。所述混悬液还可任选地包含稳定剂。
[0075]通过选择适宜的载体,本发明的局部组合物优选地被制备为油状物、乳膏、洗剂、软膏等形式。适宜的载体包括植物油或矿物油、白凡士林(白软石蜡)、支链脂类或油类、动物脂类和高分子量醇(高于C12)。优选的载体是这些活性成分在其中可溶的载体。如果需要的话,其还可以包含乳化剂、稳定剂、润湿剂和抗氧剂以及赋予其颜色或香味的物质。此外,在这些局部制剂中还可以使用经皮渗透增强剂。在US专利3,989,816和4,444,762中可以找到该类增强剂的实例。
[0076]乳膏优选地是由矿物油、自乳化的蜂蜡和水制成的,将溶解于少量油如杏仁油中的活性成分混合于该混合物中。该类乳膏的一种典型实例是一种包含约40份水、约20份蜂蜡、约40份矿物油和约1份杏仁油的乳膏。
[0077]软膏可通过将活性成分在植物油如杏仁油中的溶液与温热的软石蜡混合,然后使该混合物冷却来进行制备。该类软膏的一种典型实例是一种包含约30%重量杏仁油和约70%重量白软石蜡的软膏。
[0078]洗剂可方便地通过将活性成分溶解于适宜的高分子量醇如丙二醇或聚乙二醇中来进行制备。
[0079]下列实施例是对本发明的方法和组合物进行的举例说明,而不是限制。在临床治疗中通常会遇到对许多情况和参数进行其它适宜改变和调整的情况,其对于本领域技术人员而言都是显而易见的并且也被包括在本发明的主旨和范围中。
实施例1
基于结构对STAT3抑制剂进行的虚拟筛选
[0080]STAT3β同型二聚体的三维结构显示,Stat3β的二聚体形成发生在两个SH2区之间(图1A)(Becker等,Nature 394:145(1998);Berman等,Nucleic Acids Res.28:235(2000))。这两个SH2区通过来自各自单体的环片段(loop segment)(Ala702-Phe716)连接在一起。对Stat3β的生物学功能至关重要的磷酰酪氨酸(Y-705)位于该环片段内,它将四个相邻的氨基酸残基与另一个单体的SH2区上的空腔结合在一起。
[0081]为了鉴别可妨碍Stat3 β二聚体形成过程的小分子,将以分辨率分辨的Stat3 β的晶体结构用于此项研究(将1BG1输入到Protein Data Bank中)。从Dr.C.W.Muller处直接获得了与DNA结合的Stat3同型二聚体的三维结构。在虚拟筛选工作中使用的化学数据库包括国立癌症研究所(National Cancer Institute)(NCI)数据库、默克索引(the Merck Index)、Aldrich-Sigma产品目录和RyanScientific产品目录。总的说来,这四个数据库提供了总共将近429,000个有机化合物。公众可获得的NCI数据库本身在其内容中就提供了化合物的三维结构模型。其它三个化学产品目录只提供了它们的化合物的二维化学结构。为了解决这个问题,采用CORINA程序(2.6版本,Molecular Networks GmbH Inc.,Erlangen,Germany)来生成这三个数据库中的化合物的三维结构模型。在该过程中采用CORINA程序中的标准设置。
[0082]使用分子对接程序DOCK(4.0版本)(Ewing等,J.Comput.Aided Mol.Des.15:411(2001))来进行虚拟筛选。将Stat3 βSH2区上的结合腔定义为对接分子的靶区。使用Sybyl软件(6.9版本,Tripos Inc,St.Louise,MO)来将标准AMBER(指的是生物分子模拟的一组分子机械力字段)原子部分电荷赋值到Stat3蛋白和Gasteiger-Huckel原子部分电荷赋值到要对接的各个配体分子上。将分子量落在200到700之间的数据库中的各个分子对接,变成目标结合位点。将各个数据库中评分在前10%的化合物,如DOCK程序挑选出的那些,提取出来,结合在一起得到总共将近35,000个化合物。根据DOCK程序建议的这些化合物的结合模型,进一步应用X-评分程序(1.1版本)(Wang等,J.Comput.Aided Mol.Des.16:11(2002))以更好地估算这些化合物的结合亲和力。然后通过X-评分程序所预测的结合亲和力重新划分预先选出的35,000个化合物的等级。在X-评分程序从该化合物池挑选出的评分最好的200个化合物中,从NCI获得或从Aldrich-Sigma Corp.(St.Louis,MO)和Ryan Scientific Inc.(Isle of Palms,SC)购买其中的100个化合物。
[0083]用体外细胞萤光素酶试验(参见下面)筛选所有得到的化合物。在测试的100个化合物中,最有希望的化合物是从NCI获得的STA-21(NCI No:628869)。STA-21是天然产物提取物,是分子量为306Da(C19H14O4)的angucycline抗生素四角霉素类似物(图1D)。用DOCK程序给出STA-21的原始预期结合模型。然后用在Sybyl软件6.9版本中应用的AMBER力字段在结合位点的系统规定参数内通过结构最佳化进行改善。改善的模型显示在图1B和1C中。该模型预期STA-21在PTR残基结合的同一个位点结合,并且它可与数个临近的残基,包括Arg595、Arg609和Ile634,形成特定的氢键(图1C)。根据这个结合模型,X-评分程序预期STA-21对Stat3β SH2区具有Kd≈3μM的结合亲和力。
实施例2
STA-21对STAT3转录活性的影响
[0084]用Stat3萤光素酶报道子系统评价100个选出的抑制剂。MDA-MB-435s乳腺癌细胞和Caov-3卵巢癌细胞都表达组成性激活的Stat3(Song等,Int.J.Oncol.24:1017(2004);Song等,Biochem.Biophys.Res.Commun.314:143(2004))。通过Stat3-依赖性萤光素酶报道子pLucTKS3的稳定转染,从这两个细胞系中建立克隆细胞(Turkson等,Mol.Cell.Biol.18:2545(1998))。质粒pLucTKS3在TK最小启动子中含有Stat3-结合位点的7个拷贝,它的激活特异性地依赖于细胞环境中的Stat3状态。用Lipofectamine 2000试剂将pLucTKS3和pLucSV40萤光素酶(缺乏Stat3结合位点的对照质粒)报道子质粒转染到Caov-3和MDA-MB-435s细胞系中。选择显示出高萤光素酶活性的稳定的克隆,以筛选Stat3抑制剂。以20μM的最终浓度将所选择的克隆暴露于Stat3抑制剂48h,用Promega萤光素酶试剂盒(Madison,WI)测量萤光素酶活性。
[0085]在所测试的100个小分子中,STA-21对Caov-3克隆细胞中Stat3诱导的萤光素酶活性显示出了显著的抑制作用(图2A)。用被pLucTKS3稳定转染的MDA-MB-435s克隆细胞进一步证实STA-21对Stat3活性的抑制作用(图2B)。对MDA-MB-435s克隆细胞来说,暴露于20μM STA-2148h以后,萤光素酶活性降低超过5倍(图2B)。这表明STA-21可阻止Stat3结合到TK启动子区,并抑制克隆细胞中的萤光素酶活性。STA-21不影响不含Stat3DNA结合位点的被SV40萤光素酶报道子转染的克隆内的萤光素酶活性,这表明在缺乏Stat3DNA结合位点的情况下,STA-21本身不会降低萤光素酶活性(图2B)。作为对照,不抑制Stat3-依赖性萤光素酶活性的数个化合物显示在图2A。
实施例3
STA-21对STAT3的因子上游区和下游区的影响
[0086]接下来使用已报道的电泳迁移率变动分析来验证STA-21是否会降低Stat3DNA结合活性(Turkson等,J.Biol.Chem.276:45443(2001))。在具有组成性Stat3信号的MDA-MB-435s乳腺癌细胞中观察Stat3DNA高结合活性(图3A)。相反,在无组成性Stat3信号的MCF10A和TERT乳腺细胞没有显示出Stat3DNA结合活性。STA-21(30μM)抑制Stat3DNA结合活性(图3A)。在无组成性Stat3信号的MDA-MB-468乳腺癌细胞中,STA-21(20或30μM)也抑制下游区抗凋亡效应子Bcl-XL,如蛋白印迹分析所显示的那样(图3B)。有趣的是,Stat3上游区调节子JAK2(P-JAK2)、Src(P-Src)和EGFR(P-EGFR)的磷酸化不受STA-21的影响(图3B)。结合MDA-MB-435s细胞中Stat3而不是Stat1和Stat5DNA结合活性的STA-21抑制结果(图3A),STA-21对Stat3的抑制可通过Stat3蛋白的直接异常而达到,而不是通过抑制Stat3上游调节子。同时,STA-21不影响AKT(P-AKT)或ERK(P-ERK)的磷酸化(图3B)。
实施例4
STA-21对乳腺癌细胞的生长和存活的影响
[0087]既然STA-21抑制Stat3-依赖性萤光素酶和DNA结合活性,因此接下来验证STA-21是否抑制具有组成性Stat3信号的乳腺癌细胞的生长和存活。将细胞在20μM或30μM的STA-21中暴露48小时之后,如在细胞循环表示的凋亡细胞的亚-G1阶段中细胞积聚作用所显示的,STA-21对具有组成性激活Stat3的乳腺癌细胞系MDA-MB-231、MDA-MB-435和MDA-MB-468的存活显示了显著的抑制活性(图4B)。然而,STA-21对不具有组成性Stat3信号的MCF7和MDA-MB-453乳腺癌细胞和人皮肤成纤维细胞(HSF)具有极小的抑制作用(图4B)。通过测量磷酸化Stat3来确认细胞系的Stat3状态(图4A)。结合来自于使用MTT进行的细胞生存能力分析的数据,STA-21显示了强有效地抑制包含组成性活性Stat3的乳腺癌细胞的生长和存活。
实施例5
STA-21对STAT3易位和二聚体形成的影响
[0088]将用于表达Stat3-Flag和Stat3-HA靶向蛋白的质粒pCMV-Stat3-Flag和pCMV-Stat3-HA共转染到MDA-MB-435乳腺癌细胞中。将被转染的细胞暴露于STA-21(20μM)24小时,然后在-20°C下用100%甲醇固定30分钟。接着用磷酸盐缓冲生理盐水(PBS)洗涤3次,将抗-HA(家兔,Santa Cruz Biotechnology)和/或抗-Flag(小鼠,Sigma)抗体加入到细胞中,在37°C下培养细胞1小时。用PBS缓冲液洗涤细胞3次,将抗-家兔IgG-异硫氰酸荧光素(FITC)或/和抗-小鼠IgG-罗丹明(RHOD)的第二抗体加入,培养细胞1小时。接着用PBS洗涤3次,使用荧光显微镜观察细胞。结果显示Stat3-Flag和Stat3-HA蛋白的核易位被STA-21阻断(图5A-5G)。用FITC(绿色)和罗丹明(红色)分别染色,如图5E和5F所示,STA-21抑制了Stat3-Flag或Stat3-HA核易位。在未使用STA-21处理的细胞中,使用联合的FITC和罗丹明染色观察到了强烈的橙色染色,表明Stat3-Flag和Stat3-HA靶向的蛋白局限于细胞核中,两种颜色合并变为橙色(图5D)。然而,当所有的细胞都使用20μM的STA-21处理时,整个细胞表现出更弱的橙色染色(图5G),暗示STA-21阻断了Stat3-Flag和Stat3-HA蛋白的核易位。作为对照,DMSO用作溶剂显示对细胞没有作用。
[0089]还研究了STA-21对乳腺癌MDA-MB-435细胞中Stat3体内二聚作用的影响。暴露于20μM的STA-21 24小时后,采集细胞,将源自表达Stat3-Flag和Stat3-HA靶向蛋白的细胞的溶解产物分别与抗-Flag或抗-HA抗体进行免疫沉淀。将免疫沉淀反应混合物在10%SDS-PAGE上分离开,分别用抗-HA、抗-Flag或抗-Stat3抗体进行免疫印迹分析。结果显示在MDA-MB-435癌细胞中STA-21取消了Stat3-Flag和Stat3-HA蛋白间的二聚作用(图5H)。
现在已经对本发明进行了充分描述,本领域技术人员应当认识到其同样可以在不影响本发明范围以及其任何实施方案的情况下,在一些病症、制剂和其它参数的很宽的等同范围内来进行。本文所列举的所有专利、专利申请和公开物在这里都被全部引入作为参考。
Claims (28)
1.抑制细胞中Stat3活性的方法,包括将细胞与STA-21或其衍生物、类似物、前药或药学可接受的盐接触。
2.抑制具有增加的Stat3活性的细胞生长的方法,包括将细胞与STA-21或其衍生物、类似物、前药或药学可接受的盐接触。
3.治疗、改善或预防哺乳动物与增加的Stat3活性有关的病症的方法,包括对所述动物给药治疗有效量的STA-21或其衍生物、类似物、前药或药学可接受的盐。
4.诱导细胞中凋亡和/或细胞周期停滞的方法,包括将细胞与STA-21或其衍生物、类似物、前药或药学可接受的盐接触。
5.使细胞对凋亡诱导剂敏感的方法,包括将细胞与STA-21或其衍生物、类似物、前药或药学可接受的盐接触。
6.权利要求5的方法,进一步包括将细胞与凋亡诱导剂接触。
7.权利要求6的方法,其中,所述凋亡诱导剂是化疗剂。
8.权利要求6的方法,其中,所述凋亡诱导剂是辐射。
9.治疗、改善或预防动物中响应凋亡诱导的病症的方法,包括对所述动物给药治疗有效量的STA-21或其衍生物、类似物、前药或药学可接受的盐。
10.利要求9的方法,进一步包括施用凋亡诱导剂。
11.权利要求10的方法,其中,所述凋亡诱导剂是化疗剂。
12.权利要求10的方法,其中,所述凋亡诱导剂是辐射。
13.权利要求9的方法,其中,所述响应凋亡诱导的病症是过度增殖性疾病。
14.权利要求13的方法,其中,所述过度增殖性疾病是癌症。
15.权利要求14的方法,其中,所述癌症是乳腺癌或卵巢癌。
16.权利要求13的方法,其中,所述过度增殖性疾病是银屑病。
17.权利要求10的方法,其中,所述STA-21或其衍生物、类似物、前药或药学可接受的盐在所述凋亡诱导剂之前施用。
18.权利要求10的方法,其中,所述STA-21或其衍生物、类似物、前药或药学可接受的盐在所述凋亡诱导剂之后施用。
19.权利要求10的方法,其中,所述STA-21或其衍生物、类似物、前药或药学可接受的盐与所述凋亡诱导剂同时施用。
21.包含STA-21或其衍生物、类似物、前药或药学可接受的盐和药学可接受的载体的药物组合物。
22.包含STA-21或其衍生物、类似物、前药或药学可接受的盐和对动物施用所述化合物的说明书的药盒。
23.权利要求22的药盒,进一步包含凋亡诱导剂。
24.权利要求23的药盒,其中,所述凋亡诱导剂是化疗剂。
25.权利要求22的药盒,其中,所述说明书是为了将所述化合物施用给患有过度增殖性疾病的动物。
26.权利要求25的药盒,其中,所述过度增殖性疾病是癌症。
27.权利要求26的药盒,其中,所述癌症是乳腺癌或卵巢癌。
28.权利要求25的药盒,其中,所述过度增殖性疾病是银屑病。
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WO2015120436A2 (en) | 2014-02-10 | 2015-08-13 | H. Lee Moffitt Cancer Center And Research Institute, Inc. | Stat3 phosphorylation during graft-versus-host disease |
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JP2020520923A (ja) | 2017-05-17 | 2020-07-16 | ボストン バイオメディカル, インコーポレイテッド | がんを処置するための方法 |
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US4491588A (en) * | 1982-03-31 | 1985-01-01 | University Of Tennessee Research Corporation | Treatment of psoriasis and seborrheic dermatitis with imidazole antibiotics |
AU2736400A (en) * | 1999-01-27 | 2000-08-18 | University Of South Florida | Inhibition of stat3 signal transduction for human cancer therapy |
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- 2006-02-24 EP EP06736058A patent/EP1853242A4/en not_active Withdrawn
- 2006-02-24 US US11/361,149 patent/US20060247318A1/en not_active Abandoned
- 2006-02-24 AU AU2006216510A patent/AU2006216510A1/en not_active Abandoned
- 2006-02-24 CN CNA2006800123753A patent/CN101511179A/zh active Pending
- 2006-02-24 WO PCT/US2006/006637 patent/WO2006091837A2/en active Application Filing
- 2006-02-24 CA CA002599393A patent/CA2599393A1/en not_active Abandoned
Cited By (5)
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CN102961374A (zh) * | 2012-12-12 | 2013-03-13 | 苏州大学 | 一种化合物的应用以及stat3抑制剂 |
CN102961374B (zh) * | 2012-12-12 | 2015-01-14 | 苏州大学 | 一种化合物的应用以及stat3抑制剂 |
CN104693280A (zh) * | 2015-04-06 | 2015-06-10 | 苏州普罗达生物科技有限公司 | 信号传导及转录激活因子抑制多肽及其应用 |
CN104725480A (zh) * | 2015-04-06 | 2015-06-24 | 苏州普罗达生物科技有限公司 | 一种信号传导及转录激活因子抑制多肽及其应用 |
CN106822898A (zh) * | 2017-02-17 | 2017-06-13 | 南京九寿堂医药科技有限公司 | 靶向下调stat3基因表达在提高肺腺癌化疗敏感性方面的应用 |
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JP2008535785A (ja) | 2008-09-04 |
EP1853242A2 (en) | 2007-11-14 |
CA2599393A1 (en) | 2006-08-31 |
WO2006091837A3 (en) | 2009-04-16 |
EP1853242A4 (en) | 2009-11-18 |
US20060247318A1 (en) | 2006-11-02 |
WO2006091837A2 (en) | 2006-08-31 |
AU2006216510A1 (en) | 2006-08-31 |
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