CN102869361A - 用于治疗耐抗有丝分裂剂的癌症的n-4(-((3-(2-氨基-4-嘧啶基)-2-吡啶基)氧基)苯基)-4-(4-甲基-2-噻吩基)-1-酞嗪胺 - Google Patents
用于治疗耐抗有丝分裂剂的癌症的n-4(-((3-(2-氨基-4-嘧啶基)-2-吡啶基)氧基)苯基)-4-(4-甲基-2-噻吩基)-1-酞嗪胺 Download PDFInfo
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Abstract
本发明涉及用化合物N-(4-((3-(2-氨基-4-嘧啶基)-2-吡啶基)氧基)苯基)-4-(4-甲基-2-噻吩基)-1-酞嗪胺或其药学上可接受的盐来治疗包括实体瘤在内的癌症的方法,所述癌症已经对用化疗剂进行的治疗有抗性,所述化疗剂包括抗有丝分裂剂例如紫杉烷类和/或其它抗癌剂,包括极光激酶抑制剂。本发明亦包括通过给予癌症受试者包含所述化合物的药物组合物来治疗癌症的方法,所述癌症难以用所述治疗进行治疗。
Description
相关申请
本申请要求2009年9月11日提交的美国临时申请号61/241,527的权益,其说明书在此通过引用以其整体并入本文。
发明领域
本发明涉及N-(4-((3-(2-氨基-4-嘧啶基)-2-吡啶基)氧基)苯基)-4-(4-甲基-2-噻吩基)-1-酞嗪胺用于治疗包括实体瘤在内的癌症的用途,所述癌症已经对用抗有丝分裂剂和/或其它化疗剂进行的治疗有抗性。
发明背景
癌症是影响人类的最广泛的疾病之一,是全世界死亡的最主要原因。仅在美国,癌症仅次于心脏病是死亡的第二位原因。癌症通常表征为正常细胞过程的失调或不受调节的细胞增殖。业已转化为癌细胞的细胞易于以不受控制和不受调节的方式增殖,这在某些情况下导致癌症转移或扩散。可因对负责控制细胞周期进展的细胞途径的一个或多个基因的修饰而导致细胞增殖的失调。或者,其可因在一种或多种细胞周期关卡调节子中的DNA修饰(包括但不限于突变、扩增、重排、缺失和外遗传基因沉默)而产生,所述修饰允许细胞从细胞周期的一个阶段未经检查地进行到另一阶段。另一方式是细胞体系本身的修饰可导致有丝分裂错误,所述错误不能被恰当地检测到或修复,可允许细胞未经检查地通过细胞周期。
有丝分裂是真核细胞将其重复染色体分离为两个相同的子核的过程。其后通常紧接着胞质分裂,其将细胞核、细胞质、细胞器和细胞膜分成含有大约等份的这些细胞组分的两个子细胞。有丝分裂和胞质分裂一起确定细胞周期的有丝分裂(M)期 – 将母细胞分裂为两个子细胞,其通常是彼此相同的并与其母细胞相同。
有丝分裂过程是复杂的且受到高度调控。事件次序分为对应于一套活动结束和下一套开始的截然不同的阶段。这些阶段是分裂前期、前中期、中期、后期和末期。在有丝分裂过程中,重复染色体凝集并附着在将姐妹染色单体拉向细胞相反侧的纤维上。然后细胞以胞质分裂分裂产生两个一样的子细胞。有丝分裂中的错误可通过细胞凋亡杀死细胞,或引起染色体错误隔离,这可导致癌症。
通常若检测到DNA错误(例如DNA损伤),则激活细胞周期关卡。若基因组的这些错误不能被修复,则细胞通常经历细胞凋亡。然而,若允许细胞通过其细胞周期并不经检查地行进,那么随时间可聚积更多突变。这些基因修饰可积累,并最终通过适应导致产生具有恶化前特点或恶性瘤特点(例如不受控制地增殖)的细胞后代。
抗有丝分裂剂为抑制微管功能的抗癌剂。微管是由α-微管蛋白和β-微管蛋白异二聚体形成的蛋白多聚体,其在形成有丝分裂纺锤体和在有丝分裂末期的胞质分裂方面起着重要作用。靶向微管的抗癌剂代表用于干扰癌细胞增殖的经过验证的方法。
业已开发若干类抗有丝分裂剂作为抗癌剂。紫杉烷类是最著名的抗有丝分裂剂类别,其包括紫杉醇(泰素(taxol))和多西他赛(泰索帝(taxotere))。长春花生物碱为一类微管去稳定剂,其包括长春新碱、长春碱、长春地辛和长春瑞滨。其它新兴类别包括埃坡霉素类(伊沙匹隆)。这些抗有丝分裂剂通过稳定微管或去稳定微管起防止癌细胞增殖的作用。这种对微管的直接抑制通过细胞凋亡或有丝分裂失败导致细胞阻滞和死亡。紫杉醇是发现的紫杉烷系列的第一种化合物。随后发现紫杉醇的结构类似物多西他赛。常将紫杉醇和多西他赛用于治疗多种人恶性病,包括卵巢癌、乳腺癌、头颈癌、肺癌、胃癌、食管癌、前列腺癌和与AIDS相关的卡波西肉瘤。紫杉烷类的主要副作用是骨髓抑制,主要为嗜中性白血球减少症,而其它副作用包括外周性水肿和神经毒性(外周神经病)。
对紫杉烷类的抗性是使成功的癌症治疗复杂化的因素,通常与mdr-1编码基因的表达及其产物P-糖蛋白(P-gp)增加有关。文件记载的对紫杉烷类的获得性抗性的其它机理包括微管蛋白突变、过表达、扩增和同种型转换)。在α-或β-微管蛋白中的突变抑制紫杉烷类结合到微管的正确位置上;这使得药物无效。另外,某些抗性细胞亦显示增加的极光激酶(aurora kinase),其是一种促进有丝分裂完成的酶。
长春花生物碱(长春花(Vincas);亦称为植物生物碱)能够与微管的β-微管蛋白亚基结合,阻断其与α-微管蛋白亚基聚合形成完整微管的能力。这引起细胞周期在中期停止,导致细胞凋亡性细胞死亡,因为在缺乏完整有丝分裂纺锤体时,重复染色体不能沿分裂平面排列。研究鉴定了二聚体化的不对称长春花生物碱:长春碱、长春新碱、长春瑞滨和长春地辛,其每一种都可用于治疗癌症,所述癌症包括膀胱癌和睾丸癌、卡波西肉瘤、成神经细胞瘤和霍奇金病(Hodgkin’s disease)和肺癌及乳腺癌。长春花生物碱的主要副作用是其可在患者中引起神经毒和骨髓抑制。
在实验模型中可迅速出现对长春花生物碱的抗性。在过表达ATP-结合盒(ABC)转运蛋白介导的药物流出性转运蛋白例如P-gp和MRP1的多重耐药细胞系中,可阻断长春花生物碱的抗肿瘤作用。抗性的其它形式来源于β-微管蛋白中的突变,所述突变防止抑制剂与其靶标结合。
其它化疗剂包括拓扑异构酶抑制剂,例如伊立替康和托泊替康(I型抑制剂)和安吖啶、依托泊苷、磷酸依托泊苷和替尼泊苷(tenoposide) (II型抑制剂)。拓扑异构酶抑制剂影响DNA合成,具体而言其通过防止DNA转录和复制起作用。
再一类化疗剂为蒽环霉素抗生素类,包括柔红霉素、多柔比星、伊达比星、表柔比星和米托蒽醌。现今将蒽环霉素用于治疗很多癌症,包括淋巴瘤、白血病和子宫癌、卵巢癌、肺癌和乳腺癌。蒽环霉素通过形成游离氧自由基起作用,所述氧自由基让DNA链断裂藉此抑制DNA合成及功能。蒽环霉素的主要副作用之一,是其可损害心肌细胞,导致心脏毒性。
对包括但不限于化疗剂和抗有丝分裂剂在内的抗癌剂的抗性,已成为癌症治疗的主要障碍。所述抗性导致患者交叉抵抗很多不同药物的作用。更特别地,多重耐药是个问题。另外,这类对一种或多种抗癌治疗的抗性不可避免地导致患者死亡。因此,耐药性形成一直是所有抗癌疗法的问题,因此,仍需要鉴定不再对癌症治疗(包括用化疗剂例如紫杉烷类和长春花生物碱的传统治疗)有响应或癌症治疗仅边缘有效的癌症的治疗,以及针对监管机构批准正进行临床试验的抗癌剂。
附图简述
图1为描述AMG 900和泰素对MES-SA和MES-SA Dx5细胞系的作用(p-组蛋白H3 EC50值)的图表;
图2为描述AMG 900和泰素对NCI-H460亲代和NCI-H460泰素抗性细胞系的作用(细胞周期DNA含量EC50值)的图表;
图3为描述AMG 900和泰素对MDA-MB-231和MDA-MB-231泰素抗性细胞系的作用(细胞周期DNA含量EC50值)的图表;
图4为阐明AMG 900如何抑制已建立的MES-SA Dx5异种移植物肿瘤的生长的图表;和
图5为描述AMG 900和泰素治疗对已建立的NCI-H460-泰素抗性异种移植物生长的作用的图表;
图6为描述AMG 900对HCT116亲代、AZD1152-抗性HCT116细胞系和紫杉醇抗性细胞系的作用的的图表。
发明简述
本发明提供化合物N-(4-((3-(2-氨基-4-嘧啶基)-2-吡啶基)氧基)苯基)-4-(4-甲基-2-噻吩基)-1-酞嗪胺(本文亦称为“AMG 900”或“所述化合物”)及其药学上可接受的盐形式用于治疗晚期癌症的用途,所述癌症包括实体瘤和癌细胞,其用护理标准的政府批准的抗有丝分裂剂例如紫杉烷类(包括紫杉醇和多西他赛)和其它化疗剂难以治疗,所述其它化疗剂包括多柔比星和在治疗癌症的临床试验中给予的其它物质。AMG 900具有以下化学结构:
本发明进一步提供药物组合物用于在患者中治疗性、预防性、急性或慢性治疗癌症和癌细胞的用途,所述药物组合物包含该化合物或其药学上可接受的盐形式,所述患者先前业已用包括抗有丝分裂剂在内的化疗剂治疗。在一个实施方案中,本发明提供AMG 900在制备用于在受试者中治疗癌症的方法的药物和药物组合物中的用途,所述受试者先前业已用抗有丝分裂剂(包括有丝分裂纺锤体抑制剂和抗微管蛋白剂)或用于癌症化疗的其它药物(本文亦称为化疗剂)治疗,所述其它药物包括多柔比星、柔红霉素、更生霉素(dactinomycin)、秋水仙碱、长春碱、长春新碱、依托泊苷和米托蒽醌。在另一实施方案中,本发明提供在受试者中治疗紫杉烷抗性肿瘤类型的方法,所述肿瘤包括非小细胞肺癌、乳腺癌和激素难治疗的前列腺癌,所述方法包括给予受试者有效剂量的AMG 900或其药学上可接受的盐来治疗紫杉烷抗性肿瘤。
发明详述
发现AMG 900这种极光激酶抑制剂在人临床试验中提供优于靶向微管蛋白的目前护理标准的癌症治疗剂(例如紫杉醇、伊沙匹隆和长春花生物碱)和包括AZD1152在内的其它化疗剂(例如多柔比星)的令人惊讶和出乎意料之外的优势。具体而言,AMG 900在抑制或减慢肿瘤进展或生长方面表现出有效性,所述肿瘤通过多种提议机理交叉抵抗抗有丝分裂剂,所述机理包括例如通过ATP-结合盒(ABC)转运蛋白介导的药物流出、微管蛋白基因扩增或修饰或在α或β微管蛋白中的结构改变。另外,AMG 900靶向增殖中细胞的细胞周期的G2M期,由此不可能引起用靶向微管的抗有丝分裂剂所观察到的外周神经病。
定义
以下定义应该进一步有助于理解本文所述发明的范围。
当用于本文中时,术语"癌症"和"癌是指或阐述受试者的生理状况,所述生理状况的特征通常为不受调控的细胞生长。癌症实例包括但不限于癌、淋巴瘤、肉瘤、胚细胞瘤和白血病。所述癌症的更具体实例包括鳞状细胞癌、肺癌、胰腺癌、子宫颈癌、膀胱癌、肝细胞瘤、乳腺癌、结肠癌和头颈癌。尽管本文所用术语"癌症"不限于任何一种特定疾病形式,但认为本发明方法将对受试者的以下癌症特别有效:在某种程度上已经抵抗用抗癌剂进行的治疗的癌症,所述抗癌剂包括但不限于化疗剂、抗有丝分裂剂、蒽环霉素等等;和用所述抗癌剂治疗后复发的癌症。
当用于本文中时,术语“化疗剂”是指通过杀死癌细胞来治疗癌症。该术语另外是指用于治疗癌症的抗肿瘤药,或成为标准化治疗方案的这些药物的组合。化疗剂实例包括但不限于:烷化剂,例如顺铂、卡铂、奥沙利铂;生物碱类,包括长春花生物碱(实例包括长春新碱、长春碱、长春瑞滨和长春地辛)和紫杉烷类(实例包括紫杉醇(泰素)和多西他赛);拓扑异构酶抑制剂,例如伊立替康、托泊替康、安吖啶、依托泊苷、磷酸依托泊苷和替尼泊苷;和各种抗肿瘤剂,例如更生霉素、多柔比星、表柔比星、博来霉素和其它抗肿瘤剂。
术语"包含"意指开放式,包括所指出的组分但不排除其它成分。
当用于本文时术语“多重耐药”是指癌细胞耐受不同化学结构的多种药物和/或耐受定向不同靶标的药物。
当用于本文时术语“难治疗的”,意欲指不顺从治疗、刺激(疗法)或医治、对其抵抗或对其无反应,包括抵抗多种治疗剂。当本文在表征癌症或肿瘤上下文中使用时,“难治疗的”意欲指所述癌症或肿瘤对用一种或多种抗癌剂进行的治疗无反应或具有抗性或反应减弱。所述治疗通常在一段时间内连续、长时间和/或重复进行,导致癌症或肿瘤对完全一样的治疗发展出抗性或变得难以用完全一样的治疗进行治疗。
本文所用术语"受试者"是指任何哺乳动物,包括人和动物,例如牛、马、狗和猫。因此,本发明可在人患者以及在兽医受试者和患者中使用。在本发明的一个实施方案中,受试者为人。
短语"治疗有效的"意指确定化合物(AMG 900)的数量,所述数量相对于通过常规抗有丝分裂癌症疗法对癌症的治疗实现降低癌症或肿瘤的大小或严重程度,同时降低或避免通常与常规抗有丝分裂癌症疗法有关的有害副作用。
本文所用术语“治疗”和“处理”是指疗法,包括但不限于治愈性治疗、预防性治疗和防止性治疗。预防性治疗通常构成完全防止个体的病症发作,或延迟个体病症的临床前明显阶段的开始。
术语"药学上可接受的盐"包括常用于形成碱金属盐和形成游离酸或游离碱的加成盐的盐。盐的特性不是关键是,只要其在药学上可接受即可。可自无机酸或自有机酸制备化合物的合适的药学上可接受的酸加成盐。所述无机酸实例包括但不限于盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸和磷酸。有机酸实例包括但不限于有机酸中的脂族酸、脂环族酸、芳族酸、芳基脂族酸、杂环酸、羧酸和磺酸类,其实例为甲酸、乙酸、己二酸、丁酸、丙酸、琥珀酸、乙醇酸、葡糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡糖醛酸、马来酸、富马酸、丙酮酸、天冬氨酸、谷氨酸、苯甲酸、邻氨基苯甲酸、甲磺酸(mesylic acid)、4-羟基苯甲酸、苯乙酸、扁桃酸、双羟萘酸(扑酸)、甲磺酸(methanesulfonic acid)、乙磺酸、乙二磺酸、苯磺酸、泛酸、2-羟基乙磺酸、甲苯磺酸、对氨基苯磺酸、环己基氨基磺酸、樟脑酸、樟脑磺酸、二葡萄糖酸(digluconic acid)、环戊烷丙酸、十二烷基磺酸、葡庚糖酸、甘油磷酸、庚酸、己酸、2-羟基-乙磺酸、烟酸、2-萘磺酸、草酸、棕榈酸、果胶酸(pectinic acid)、过硫酸、2-苯基丙酸、苦味酸、新戊酸丙酸、琥珀酸、酒石酸、硫氰酸、甲磺酸、十一烷酸、硬脂酸、藻酸(algenic acid)、β-羟基丁酸、水杨酸、粘酸和半乳糖醛酸。
化合物的合适的药学上可接受的碱加成盐包括但不限于:金属盐,例如自铝、钙、锂、镁、钾、钠和锌制备的盐;或自有机碱制备的盐,所述有机碱包括伯胺、仲胺、叔胺和取代胺,包括环胺,例如咖啡因、精氨酸、二乙胺、N-乙基哌啶、aistidine、葡糖胺、异丙胺、赖氨酸、吗啉、N-乙基吗啉、哌嗪、哌啶、三乙胺、三甲胺。本文考虑的所有盐都可通过常规手段自相应化合物通过例如适当的酸或碱与所述化合物反应来制备。
可通过与PCT公开号WO2007087276中第70页实施例方法A1或A2类似的程序但用1-氯-4-(4-甲基-2-噻吩基)酞嗪作为原料,联合实施例15 (第50页)、25 (第55页)和30 (第59页)来制备AMG 900, 即N-(4-((3-(2-氨基-4-嘧啶基)-2-吡啶基)氧基)苯基)-4-(4-甲基-2-噻吩基)-1-酞嗪胺。这些程序亦在美国专利号7,560,551中阐述,其说明书通过引用以其整体在此并入本文中。AMG 900具体地可如以下实施例1所述来制备。
实施例1
合成N-(4-((3-(2-氨基-4-嘧啶基)-2-吡啶基)氧基)苯基)-4-(4-甲基-2-噻吩基)-1-酞嗪胺(AMG 900)
步骤1:4-(2-氯吡啶-3-基)嘧啶-2-胺
在置于异丙醇浴中的氩气净化的500 mL圆底烧瓶中,将金属钠(3.40g, 148毫摩尔)缓慢加入到甲醇(180mL)中。于室温(RT)搅拌混合物约30分钟。向其中加入盐酸胍(12.0 mL, 182毫摩尔),在RT将混合物再搅拌30分钟,接着加入(E)-1-(2-氯吡啶-3-基)-3-(二甲基氨基)丙-2-烯-1-酮(12.0 g, 57.0毫摩尔),连接空气冷凝器,将反应移到油浴中,在此其加热到约50℃达24小时。减压下蒸发大约一半甲醇,真空下过滤固体,然后用饱和碳酸氢钠(NaHCO3)和H2O洗涤,风干得到4-(2-氯吡啶-3-基)嘧啶-2-胺,为灰白色固体。MS m/z = 207 [M+1]+。C9H7ClN4计算值:206.63。
步骤2:4-(2-(4-氨基苯氧基)吡啶-3-基)嘧啶-2-胺
向可再密封的管中加入4-氨基苯酚(1.3 g, 12毫摩尔)、碳酸铯(7.8 g, 24毫摩尔)和DMSO (16 ml, 0.75 M)。将混合物加热到100℃达5分钟,然后加入4-(2-氯吡啶-3-基)嘧啶-2-胺(2.5 g, 12毫摩尔),将反应混合物加热到130℃过夜。完成(如通过LCMS所鉴定)后,使反应混合物冷却到RT,用水稀释。过滤得到的沉淀物,用水和二乙醚洗涤固体。然后在9:1的CH2Cl2:MeOH中溶解固体,用9:1的CH2Cl2:MeOH作为洗脱液通过硅胶垫。真空浓缩溶剂,得到期需产物4-(2-(4-氨基苯氧基)吡啶-3-基)嘧啶-2-胺。MS m/z = 280 [M+1]+。C15H13N5O计算值:279.30。
步骤3:1-氯-4-(4-甲基噻吩-2-基)酞嗪
将1,4-二氯酞嗪(1.40 g, 7.03毫摩尔)、4-甲基噻吩-2-基硼酸(999 mg, 7.03毫摩尔)和PdCl2(DPPF) (721 mg, 985 μmol)加入到密封管中。用氩气净化管。然后加入碳酸钠(2.0 M,水中) (7.74 ml, 15.5毫摩尔)和1,4-二噁烷(35.2 ml, 7.03毫摩尔)。密封管,在RT搅拌5分钟,置于预热的110℃油浴中。1小时后,LC-MS显示产物和副产物(双偶联)和原料二氯酞嗪。让反应冷却到RT,借助乙酸乙酯(EtOAc)通过硅藻土垫过滤,浓缩,上样到柱上。通过柱色谱来纯化产物,该柱色谱用Hex除去顶部污迹然后用80:20的己烷:EtOAc收集产物。获得产物1-氯-4-(4-甲基噻吩-2-基)酞嗪,为黄色固体。LC-MS显示产物污染有少量二氯酞嗪和双偶联副产物。MS m/z = 261 [M+1]+。C13H9ClN2S计算值:260.12。
步骤4:N-(4-((3-(2-氨基-4-嘧啶基)-2-吡啶基)氧基)苯基)-4-(4-甲基-2-噻吩基)-1-酞嗪胺
向4-(2-(4-氨基苯氧基)吡啶-3-基)嘧啶-2-胺和1-氯-4-(4-甲基-2-噻吩基)酞嗪中加入tBuOH。在密封管中让得到的混合物于100℃加热16小时。用二乙醚和饱和碳酸钠稀释反应物,并剧烈震荡。过滤得到的固体,用水、二乙醚洗涤,晾干得到N-(4-((3-(2-氨基-4-嘧啶基)-2-吡啶基)氧基)苯基)-4-(4-甲基-2-噻吩基)-1-酞嗪胺,为灰白色固体。MS m/z = 504 [M+H]+。C28 H21 N7 O S计算值:503.58。
LC-MS方法:
在具Agilent Technologies XDB-C8 (3.5 μ)反相柱(4.6 x 75 mm)的Agilent模型-1100 LC-MSD系统中于30℃处理样品。流速恒定,范围为约0.75 mL/分钟-约1.0 mL/分钟。
流动相使用溶剂A (H2O/0.1% HOAc)和溶剂B (AcCN/0.1% HOAc)的混合物,和9分钟时间的10%-90%溶剂B的梯度。梯度接着在0.5分钟时间回到10%溶剂B,用10%溶剂B再平衡(冲洗)柱2.5分钟。
亦可将其它方法用于合成AMG 900。可用于合成AMG 900的许多合成化学转化以及保护基方法为本领域所知。有用的有机化学转化文献包括例如:R. Larock, Comprehensive Organic Transformations, VCH出版社(1989);T.W. Greene和P.G.M. Wuts, Protective Groups in Organic Synthesis, 第3版, John Wiley和Sons (1999);L. Fieser和M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley和Sons (1994);A. Katritzky和A. Pozharski, Handbook of Heterocyclic Chemistry, 第2版(2001);M. Bodanszky, A. Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag, Berlin Heidelberg (1984);J. Seyden-Penne, Reductions by the Alumino- and Borohydrides in Organic Synthesis, 第2版, Wiley-VCH, (1997);和L. Paquette,编辑, Encyclopedia of Reagents for Organic Synthesis, John Wiley和Sons (1995)。
在各种细胞系(体外)和多种实体瘤类型(体内)中测定AMG 900降低或抑制肿瘤进展的能力,所述细胞系和实体瘤中的一些先前业已接触护理标准的抗有丝分裂剂(包括紫杉烷类和长春花生物碱)以及其它化疗剂,或对其产生了抗性。以下实施例及得到的数据表明AMG 900治疗癌症的能力,所述癌症包括耐受目前护理标准疗法包括抗有丝分裂剂(例如紫杉醇)和与化疗联合使用的其它药物(例如多柔比星)的癌症。除非另外指出,否则在下文所述实施例中使用AMG 900的游离碱形式。
实施例2
为了研究AMG 900诱导的极光激酶A和B活性的抑制是否抑制细胞增殖,在体外用32种人肿瘤细胞系评估了AMG 900的抗增殖作用。如表1和表2所示,AMG 900对实体瘤和血液学肿瘤细胞系二者都表现出抗增殖活性。这种抗增殖活性在低纳摩尔范围(EC50值1-5 nM)的AMG 900浓度中观察到。重要的是,这些AMG 900敏感的实体瘤细胞系中的四种(HCT15、MES-SA Dx5、769P和SNU449)对紫杉醇和其它化疗剂有抗性。将抵抗不同化学结构的多种药物和/或抵抗定向不同靶标的药物的癌细胞命名为“多重耐药”。癌细胞利用的多重耐药(MDR)的一种著名机理是通过ATP-结合盒(ABC)转运蛋白家族介导的药物流出,所述ATP-结合盒(ABC)转运蛋白为例如mdr-1基因产物、P-糖蛋白(P-gp)。例如,耐多柔比星的人子宫细胞系MES-SA Dx5表达P-gp,抵抗(为亲代细胞系的30-1200倍)多种化疗剂,包括柔红霉素、更生霉素、秋水仙碱、长春碱、长春新碱、紫杉醇、依托泊苷和米托蒽醌。为了进一步研究AMG 900在MDR表达细胞中的活性,测定了三种泰素抗性肿瘤细胞系,并与其各自的亲代细胞系进行了比较。如图1-3和表3所示,AMG 900在所有三种匹配的泰素抗性和泰素敏感性肿瘤细胞系中以EC50值< 2 nM保持功效。与亲代细胞系比较,在表达P-gp的肿瘤亚系中泰素显示明显的功效损失(10倍到100倍)。综合这些数据,表明AMG 900抑制磷酸化组蛋白H3 (极光激酶B的近似底物),并阻断耐紫杉醇和其它化疗剂的肿瘤细胞系的细胞分裂。
材料和方法
关键试剂
洗涤液和固定液
试剂
实验室设备、补给品、软件
台式冷冻离心机 | Allegra X-15R离心机, Beckman Coulter, Fullerton, CA 92834 |
GraFit v5软件 | Erithacus Software, Horley Surrey, RH6 9YJ, UK |
XLfit 4.2软件 | Excel, Microsoft Inc., USA |
GraphPad Prism v5 | GraphPad Software, Inc.2236 Avenida de la Playa, La Jolla, CA 92037 |
流式细胞仪 | Becton Dickinson LSRII流式细胞仪, BD Biosciences, San Jose, CA 95131 |
96-孔组织培养板, 平底低蒸发盖,无菌 | 目录号3595, 批号未提供, Corning Incorp. Life Sciences, Lowell MA 01851 |
12-孔组织培养板, 平底低蒸发盖, 无菌 | 目录号353043, 批号未提供, BD Labware, Franklin Lakes, NJ 07417 |
6-孔组织培养板, 平底低蒸发盖, 无菌 | 目录号353046, 批号未提供, BD Labware, Franklin Lakes, NJ 07417 |
用于FACS染色的PCR条形管(tube Strip) | 目录号20170-004, 批号 711C7-7074, 用于PCR的0.2 mL 条形管(strip tube), VWR Intl., West Chester, PA 19380. |
1.5mL Eppendorf管 | 目录号20901-551, 未提供批号, VWR Intl., West Chester, PA 19380 |
Packard View-96孔板 | 目录号-6005182, 未提供批号, PerkinElmer Life andAnalytical Sciences, Waltham, MA 02451 |
ELX405洗板机 | 目录号ELX405HT, BioTek, Winooski, VT 05404 |
Multidrop DW(深孔) | 目录号5840177, Thermo Fisher Scientific Inc, Waltham, MA 02454 |
Cellomics Array Scan VTi | Cellomics-Thermo Fisher Inc, Waltham, MA 02454 |
方法
体外在源自子宫、乳腺和肺组织的亲代和耐药性肿瘤细胞系中评估AMG 900的活性。分别通过流式细胞术和高容量细胞成像评估细胞周期和p-组蛋白H3终点。
人细胞和细胞培养
除非另外指出,否则人肿瘤细胞系自美国典型培养物保藏中心(Manassas, VA)获得。所有细胞于37摄氏度保持在5% CO2气氛中。自DSMZ (GmbH)获得源自乳腺肿瘤的CAL51 (ACC 302)细胞系。在许可下自约翰霍普金斯大学遗传学资源核心设施(John Hopkins University Genetics Resources Core Facility)获得源自结肠肿瘤的HCT-116_JH (基因型p21+/+)和HCT-116_JH (基因型p21-/-)细胞系。
人肿瘤细胞系与相应培养基
用AMG 900处理的实体瘤细胞系组:抗增殖测定(ArrayScan VTi)
视细胞系生长动力学(大体上定义为慢与快)而定以3000或5000个细胞/孔的密度,将肿瘤细胞接种在含100 μL合适的完全培养基的Packard View 96-孔板中。用Biomek FX工作站实施所有稀释。第二天用AMG 900 (11点剂量范围为0.156-0.0003 μM)处理细胞,培养基中的最终DMSO浓度为0.12%。24小时后,移走含有化合物的培养基,用完全培养基洗涤细胞。然后在100 μL新鲜的完全培养基(无化合物)中让细胞孵育48小时。48小时后,通过将100 μL固定缓冲液加到100 μL完全培养基中来固定细胞。让细胞在室温孵育10分钟。吹吸固定缓冲液,然后在100 μL洗涤缓冲液中于室温达30分钟使细胞透化,接着加入100 μL DNA染色缓冲液,在黑暗中于室温孵育30分钟。接下来,用100 μL洗涤缓冲液洗涤细胞,并于4摄氏度储存在100 μL 1x PBS中直到分析。通过在ArrayScan VTi成像系统(Cellomics)上扫描96-孔板获得细胞数据。基于Hoechst 33342 DNA染料荧光实施单个细胞核面积及强度的定量。基于DMSO处理的对照孔设定细胞核面积的阀值,以根据细胞核碎片和多倍体细胞定量正常大小的细胞核的数目。应用该阀值,用10x放大倍数以6个像视野/孔计数正常细胞核的数目。用4-参数方程计算剂量-浓度曲线和EC50值。
用AMG 900处理的血液学细胞系组:多参数细胞周期DNA含量测定(流式细胞术)
以100,000个细胞/孔的密度,将肿瘤细胞接种在含150 μL合适的完全培养基的300 μL深96-孔板中。用AMG 900 (11点剂量范围为0.156-0.0003 μM)处理细胞,培养基中的最终DMSO浓度为0.2%。在收获之前的2小时,用BrdU以培养基中1:100的终浓度脉冲细胞。48小时后,用多孔移液器从每孔移走100 μL培养基。然后将细胞转移到含200 μL培养基的PCR条形管中。以2000 rpm在18℃让细胞离心4分钟,吸走上清液。然后在200 μL冰冷的90%甲醇中固定细胞,在抗体和DNA染色之前贮存在–20℃至少24小时。以2000 rpm让固定的细胞离心4分钟以除掉90%甲醇。用200 μL洗涤缓冲液洗涤细胞,然后用100 μL酸性缓冲液在室温于黑暗中处理1小时。用200 μL洗涤缓冲液洗涤细胞2次(直到pH为7.0,用pH试纸确定)。让细胞与抗BrdU-Alexa 647 (3 μg/mL)和抗胱天蛋白酶 3-FITC (20 μl/孔)抗体混合物在洗涤缓冲液中于室温黑暗中孵育2小时。让染色的细胞离心,用200 μL洗涤缓冲液洗涤。用200 μL碘化丙锭(PI)于4℃黑暗中过夜复染细胞。通过流式细胞仪(LSRII)获得并分析数据。基于DMSO对照和低/高药物处理组,按照DNA含量、BrdU和胱天蛋白酶-3阳性/阴性群应用阀门。数据表示为SubG1 DNA含量、4N+DNA含量、BrdU和胱天蛋白酶-3裂解阳性群的百分比。用4-参数方程计算浓度-反应曲线和EC50值。
用AMG 900或紫杉醇(泰素)处理的MES-SA Dx5和MES-SA细胞系:p-组蛋白H3测定(ArrayScan VTi)
以10,000个细胞/孔的密度在含完全培养基的96-孔板中让MES-SA Dx5和MES-SA细胞铺板,并培养24小时。第二天用AMG 900或泰素在10点浓度范围(1.25 μM-0.0024 μM)内处理细胞24小时,培养基中的最终DMSO浓度为0.1%。洗涤细胞,通过加入100 μL的2x甲醛固定缓冲液在室温固定10分钟。洗涤细胞,用100 μL洗涤缓冲液持续15分钟使细胞透化。用p-组蛋白H3抗体(5 μg/mL)免疫染色细胞,在室温孵育2小时。在100 μL洗涤缓冲液中洗涤细胞。接下来,让细胞与山羊抗兔alexa-488缀合抗体(1.5 μg/mL)在补充有Hoechest DNA染料(1 μg/mL)的洗涤缓冲液中孵育,并于室温黑暗中孵育30分钟。用100 μL洗涤缓冲液洗涤细胞2次。在ArrayScan VTi (Cellomics)上用生物应用算法(TargetActivation.V2)分析96-孔板。p-组蛋白H3+对象(用10x物镜进行的6个像视野/孔的总和)的百分比用于产生浓度-反应曲线,用4-参数方程计算EC50值。
用AMG 900或紫杉醇(泰素)处理的NCI-H460亲代和泰素抗性细胞系:细胞周期DNA含量测定(流式细胞术)
以500,000个细胞/孔的密度在含2 mL合适的完全培养基的6-孔板中接种NCI-H460亲代和NCI-H460泰素抗性细胞。第二天用AMG 900或泰素在6点浓度范围内处理细胞,培养基中的最终DMSO浓度为0.05%。24小时后,用BrdU (1:100稀释)脉冲细胞并收获细胞。以1600 rpm让细胞离心4分钟,吸取上清液。在1x PBS中洗涤细胞,并在900 μL冰冷的90%甲醇中固定,贮存在–20℃。让固定的细胞以2000 rpm离心4分钟,以去掉90%甲醇。用200 μL洗涤缓冲液洗涤细胞和用200 μL碘化丙锭(PI)在4℃黑暗中过夜染色。通过流式细胞术(LSRII)获得并分析数据。基于DMSO处理对照和低/高药物处理组,按照+4N (等同于≥ 4N) DNA含量和SubG1阳性群应用阀门。数据表示为+4N DNA和SubG1阳性亚群的百分比。用4-参数方程计算+4N (等同于≥ 4N) DNA含量或SubG1细胞EC50值。
用AMG 900或紫杉醇(泰素)处理的MDA-MB-231 (F11)-luc亲代和泰素抗性细胞系:细胞周期DNA含量测定(流式细胞术)
以250,000个细胞/孔的密度在含1 mL合适的培养基的12-孔板中一式二份接种MDA-MB-231(F11)-luc亲代和泰素抗性细胞。第二天用AMG 900或泰素在10点浓度范围内处理细胞,无泰素培养基中的最终DMSO浓度为0.1%。24小时后,用1x胰蛋白酶-EDTA收获细胞,并转移到 PCR管。让细胞以2000 rpm离心4分钟,吸取上清液。在200 μL冰冷的90%甲醇中固定细胞,并贮存在–20℃至少24小时。让固定的细胞以2000 rpm离心4分钟,以除去90%甲醇。用洗涤缓冲液洗涤细胞,并用200 μL碘化丙锭(PI)在4℃黑暗中染色30分钟。在获得数据前再加入400 μL的PI。通过流式细胞术(LSRII)获得并分析数据。基于DMSO对照和低/高药物处理组,按照+4N (等同于≥ 4N) DNA含量应用阀门。数据表示为+4N DNA含量阳性群的对照的百分比。用4-参数方程确定+4N DNA含量细胞的EC50值。
表1 体外AMG 900抑制多种实体瘤类型的细胞增殖
肿瘤细胞系 | 来源 | AMG 900 EC50 (μM) |
HCT 116_JH_p21-/- | 结肠 | 0.001 |
HCT 116_JH_p21+/+ | 结肠 | 0.001 |
HCT15* | 结肠 | 0.002 |
HT29 | 结肠 | 0.005 |
SW620 | 结肠 | 0.002 |
SW480 | 结肠 | 0.002 |
HOP-92 | 肺 | 0.002 |
HOP-62 | 肺 | 0.002 |
NCI-H460 | 肺 | 0.001 |
A549 | 肺 | 0.001 |
PC3 | 前列腺 | 0.002 |
DU145 | 前列腺 | 0.002 |
BT549 | 乳腺 | 0.004 |
MDA-MB-231 | 乳腺 | 0.002 |
T47D | 乳腺 | 0.005 |
MCF7-p53+ | 乳腺 | 0.001 |
MCF7-p53- | 乳腺 | 0.003 |
CAL51 | 乳腺 | 0.002 |
SK-OV-3 | 卵巢 | 0.002 |
MES-SA Dx5* | 子宫 | 0.001 |
SK-MEL-2 | 皮肤 | 0.002 |
A498 | 肾脏 | 0.001 |
769P* | 肾脏 | 0.002 |
CAKI-1 | 肾脏 | 0.001 |
SK-HEP-1 | 肝脏 | 0.001 |
SNU449* | 肝脏 | 0.002 |
*紫杉醇抗性肿瘤细胞系(Gyorffy等, 2006;
Harker, G.A.等. Multidrug (Pleiotropic) Resistance in Doxorubicin-selected Variants of Human Sarcoma Cell Line MES-SA (多柔比星选择的人肉瘤细胞系MES-SA变体中的多重耐药物(多效性抗性)). Cancer Research 1985: 45: 4091-4096;
Szakacs, G.等. Predicting drug sensitivity and resistance: Profiling ABC transporter genes in cancer cells (预测药物敏感性和抗性:对癌细胞中的ABC转运蛋白基因进行概况分析). Cancer Cell 2004: 6: 129-137;
Szakacs, G.等. Targeting multi-drug resistance in cancer (靶向癌症中的多重耐药). Nat. Rev. Drug Discovery 2006: 5: 219-234
表2 AMG 900在体外阻断几种血液学肿瘤类型的细胞分裂
用AMG 900处理细胞48小时(无化合物撤回)。用多终点(胱天蛋白酶-3裂解、BrdU、SubG1和+4N DNA含量(≥4N DNA含量))实施基于流式细胞术的分析。用+4N DNA含量终点产生EC50值。报告的EC50值代表单个10-点剂量-反应曲线。
表3 在体外AMG 900在耐紫杉醇的肿瘤细胞系中保持功效
抗性(r)定义为与亲代细胞系比较,在亚系中≥10倍的功效(EC50值)损失。
a基于Cellomics的p-组蛋白H3分析。报告的EC50值代表用10-点剂量反应实施的单一实验。
b基于流式细胞术的DNA含量分析。用合适的DNA含量终点(≥4N DNA含量(AMG 900)和Sub G1 (紫杉醇))产生EC50值。EC50值代表用10-点剂量反应一式二份实施的单一实验。MDA-MB-231细胞系含有表达绿色荧光蛋白和萤光素酶蛋白二者的转基因。
c基于流式细胞术的DNA含量分析。用合适的DNA含量终点(≥4N DNA含量(AMG 900)和Sub G1 (紫杉醇))产生EC50值。EC50值代表用6-点剂量反应实施的单一实验。
1通过让细胞在渐增浓度的多柔比星存在下生长,自亲代MES-SA细胞系建立多重耐药亚系MES-SA Dx5。MES-SA Dx5细胞系过表达P-gp (Harker等, 1985)。
2通过让细胞在渐增浓度的紫杉醇存在下生长,自其各自亲代细胞系获得紫杉醇抗性亚系MDA-MB-231-泰素抗性和NCI-H460-泰素抗性。根据流式细胞术,两种亚系皆为P-gp阳性。
图1:AMG 900和泰素对MES-SA和MES-SA Dx5细胞系的作用,p-组蛋白H3 EC50值
用对照(DMSO)、AMG 900或紫杉醇(泰素)在10-点剂量范围(0.0024-1.25 μM)内处理子宫肿瘤细胞系24小时。然后用p-组蛋白H3抗体固定和染色细胞,并用DNA染料(Hoechest)复染。实施基于图像的分析(ArrayScan VTi)以测量p-组蛋白H3阳性细胞的百分比。剂量-反应曲线代表针对作为DMSO处理的对照的百分比(POC)的p-组蛋白H3阳性细胞作图的AMG 900或泰素浓度。通过4-参数拟合模型计算EC50值。
图2:AMG 900和泰素对NCI-H460亲代和NCI-H460泰素抗性细胞系的作用,细胞周期DNA含量EC50值
用对照(DMSO)、AMG 900或紫杉醇在6-点剂量范围内处理肺肿瘤细胞系24小时。实施基于流式细胞术的细胞周期分析,以测量≥4N DNA含量或SubG1 DNA含量阳性细胞的百分比。AMG 900的剂量-反应曲线代表对≥4N DNA含量阳性细胞的百分比作图的药物浓度。泰素的剂量-反应曲线代表对SubG1 DNA含量阳性细胞的百分比作图的药物浓度。通过4-参数拟合模型计算EC50值。
图3:AMG 900和泰素对MDA-MB-231和MDA-MB-231泰素抗性细胞系的作用,细胞周期DNA含量EC
50
值
用对照(DMSO)、AMG 900或泰素在10-点剂量范围内处理乳腺肿瘤细胞系24小时。实施基于流式细胞术的细胞周期分析,以测量≥4N DNA含量或SubG1 DNA含量阳性细胞的百分比。AMG 900的剂量-反应曲线代表对≥4N DNA含量阳性细胞的百分比作图的药物浓度。泰素的剂量-反应曲线代表对SubG1 DNA含量阳性细胞的百分比作图的药物浓度。通过4-参数拟合模型计算EC50值。
实施例3
为了研究AMG 900诱导的极光激酶活性抑制是否抑制细胞增殖,体内在无胸腺裸小鼠中生长的多种人癌症异种移植物模型中评估了AMG 900的抗增殖功效,所述多种人癌症异种移植物模型包括乳腺、结肠、白血病、肺、胰腺和子宫癌症模型。当建立肿瘤时开始的研究期间,每周连续2天以3.75、7.5或15 mg/kg每天两次或每天以3 mg/kg每天两次经口给予小鼠AMG 900。试剂、溶液、设备、AMG 900制剂、肿瘤体积测量和计算大体如以下实施例4所述。发现与溶媒对照组比较,在所测试的所有异种移植物模型中,AMG 900显著抑制肿瘤生长(表4)。
表4. AMG 900抑制多种异种移植物模型的生长
(TGI)肿瘤生长抑制, *%TGI挑选自基于最佳功效反应的间歇性或连续性给药方案;
(ND)未确定的,抗性(r)定义为与紫杉烷敏感性肿瘤细胞系相比的≥10倍的效力(EC50值)损失
对作为肿瘤异种移植物在体内生长的多重耐药细胞系MES-SA Dx5测定AMG 900的作用。在研究期间每周连续2天以15 mg/kg每天两次或每天以3.0 mg/kg每天两次经口给予小鼠AMG 900。当建立肿瘤时(肿瘤植入后10天)开始给药。与溶媒对照组比较,使用两种AMG 900的剂量和方案的AMG 900治疗都导致统计学显著的肿瘤生长抑制(图4;p < 0.0001, Dunnett事后检验)。在2种其它耐药性模型(HCT15和NCI-H460-泰素抗性[r])中用相似的治疗方案亦令人惊讶地实现可比拟的肿瘤生长抑制(参见表4)。
图4:AMG 900抑制已建立的MES-SA Dx5异种移植物肿瘤的生长
将MES-SA Dx5这种多重耐药细胞(2 x 106)在雌性无胸腺裸小鼠右侧腹皮下注射。每周测量两次肿瘤。第10天开始治疗,此时肿瘤为约100 mm3。用AMG 900 (每天两次)间歇或连续口服给予小鼠。在整个研究期间每日为所有组提供营养补充品以保持体重。每个组的数据代表平均值± SEM (n = 10/组)。P-值对应于用溶媒和AMG 900治疗的组之间的统计学差异,其通过RMANOVA接着Dunnett事后检验来确定。箭头表示给药开始。
实施例4
为了研究AMG 900诱导的极光激酶活性抑制是否抑制细胞增殖,在体内针对无胸腺裸小鼠中的NCI-H460-泰素抗性肿瘤异种移植物评估了AMG 900的抗肿瘤功效。用AMG 900 (每天两次)间歇或连续口服给予小鼠。用紫杉醇(泰素) 5天/周腹膜内给予小鼠。在本研究中用内部Amgen化合物作为阳性对照(数据未显示)。每周测量2次肿瘤,第12天开始治疗,此时已建立肿瘤。在整个研究期间每日为所有组提供营养补充品以保持体重。
动物和组织
制剂
将AMG 900 (游离碱)调配为浓度为1.5和0.3 mg/mL的混悬液。给药体积等于10 mL/kg。泰素(Bristol Meyers Squibb)在市购自Burt’s Pharmacy (Newbury Park, CA),每日自6 mg/mL储液浓度稀释为1.25 mg/mL的工作浓度。
治疗方案
组别 | n | 途径 | 治疗 | 剂量(mg/kg) | 方案 |
1 | 10 | 口服 | 溶媒 | - | 每天两次,7天/周 x 3周 |
2 | 10 | 口服 | AMG 900 | 3 | 每天两次,7天/周 x 3周 |
3 | 10 | 口服 | AMG 900 | 15 | 每天两次,2天给药/5天休息/周 x 3周 |
4 | 10 | 腹膜内 | 泰素 | 12.5 | 每天一次,5天/周 x 2周 |
AMG 900的给药期持续时间为3周,泰素组为2周。用数显卡尺测量肿瘤,每周称量小鼠2次。肿瘤体积如下计算:肿瘤体积(mm3) = [(W2 X L)/2],其中宽度(W)定义为2个测量值的较小的一个,长度(L)定义为2个测量值的较大的一个。肿瘤抑制如下计算:首先对于对照和所有治疗组,用初始肿瘤体积减去最终肿瘤体积;其次,用治疗的肿瘤体积的变化除以对照肿瘤体积,减去1然后乘以100。下文表5和图5阐述肿瘤体积和肿瘤生长抑制结果。
表5. 肿瘤体积数据概述
组别 | 平均值 | SE | 抑制% | 中值 |
溶媒(HPMC)口服每天两次,7天 | 1680 | 215 | 0.0 | 1749.7 |
AMG 900 3mpk口服每天两次,7天 | 771 | 104 | 60.4 | 715.6 |
AMG 900 15mpk口服每天两次,2天 | 689 | 107 | 65.7 | 612.5 |
泰素12.5mpk腹膜内每天一次,5天 | 1383 | 283 | 19.7 | 1072.0 |
图5:AMG 900和泰素治疗对已建立的H460-泰素抗性异种移植物生长的作用
图5阐明AMG 900和泰素治疗对已建立的H460-泰素抗性肿瘤生长的作用。在雌性裸小鼠(n = 10/组)右侧腹皮下注射细胞(2 x 106/动物)。每周测量肿瘤两次。在肿瘤植入后12天开始治疗(箭头),此时肿瘤为约170 mm3。每日一次或2次给小鼠口服或腹膜内给药,持续3周。每一组的数据代表平均值± SEM。*P值(未显示)对应于用溶媒和AMG 900或泰素治疗的组之间的统计学差异,其随时间用STATview以重复测量Sheffe氏ANOVA来分析。图例中所列的计划天数代表天/周。在整个研究期间给所有组提供营养补充品。
如上图5所阐明,当连续(3 mg/kg每天两次达7天(60%抑制, p = 0.0003))或间歇(15 mg/kg每天两次,2天给药/5天休息/周(66%抑制, p < 0.0001))给予时,用AMG 900治疗荷瘤小鼠明显抑制肿瘤生长。当在本实验中以12.5 mg/kg腹膜内5天/周达两个给药周期给药时,泰素不能显著抑制肿瘤生长(20%抑制, p = 0.5399)。
令人惊讶并意外地发现,AMG 900在抵抗以下三种充分表征的极光激酶抑制剂的肿瘤细胞系中保持活性:AZD1152;VX-680 (通常亦称为MK-0457);和PHA-739358 (Danusertib)。这些实验中使用的抑制剂为文献中公开并表征的化合物。例如,参见Expert Opinion Investigational Drugs (2009) 18 (4)第379-398页;Expert Opinion Therapeutic Patents, (2009) 19 (3), 第321-356页。在Steeghs等, Journal of Clinical Oncology, 27, 2009中可获得Danusertib (PHA-739358)在晚期或转移实体瘤患者中于I期的详细安全性、耐受性及pK曲线,包括化学结构。
以下提出的数据指出与上述三种著名的极光激酶抑制剂在泰素抗性细胞系中抑制组蛋白H3磷酸化的能力相比的AMG 900在相同的泰素抗性细胞系中的活性。
实施例5
在表达P-gp或BCRP药物流出转运蛋白的MDR肿瘤细胞系亚类中评估三种极光激酶抑制剂(AZD1152、MK-0457和PHA-739358)。令人意外的是,不管P-gp或BCRP状态怎样,AMG 900都以一致的IC50或EC50值(2-3纳摩尔/L)在所测试的所有细胞系中抑制p-组蛋白H3或诱导多倍体。与此相反,如下表6所示,与匹配的敏感肿瘤细胞系相比,其它极光激酶抑制剂在一种或多种MDR细胞系中效力较小。
材料和方法
化合物材料:以下化合物的分子结构可在公有领域获得:紫杉醇和多西他赛、MLN8054、MK-0457、AZD1152和PHA-739358。材料购自商业来源,适用时,紫杉烷类亦是如此。
细胞系:除非另外规定,否则自美国典型培养物保藏中心(ATCC)获得肿瘤细胞系。通过6个月期间在渐增浓度的紫杉醇存在下让细胞生长来建立MDA-MB-231-PTX和NCI-H460-PTX细胞系。通过在80纳摩尔/L的AZD1152存在下让细胞生长来建立HCT116 AZD1152-抗性细胞系。
动物:按照动物护理及使用委员会(Institutional Animal Care and Use Committee)和美国农业部的规章实施所有实验程序。将四-六周龄的雌性无胸腺裸小鼠(Harlan Sprague Dawley)安置在消毒的笼中,并保持在无菌条件下。安置动物的实验室提供交替明暗周期(各自12小时),并满足实验室动物护理评估和认证协会的规范标准。随意提供食物、水和营养补充品。基于每只小鼠的个体体重给予所有药物。
基于荧光的细胞成像测定:在ArrayScan VTi HCS Reader(Cellomics)上进行所有高含量细胞测定。用AMG 900、AZD1152、MK-0457或PHA-739358 (基于效力改变浓度范围)处理肿瘤细胞系。制备细胞用于如前述用抗p-组蛋白H3 Ser10抗体进行的细胞内染色(1)。用抗兔IgG-alexa-568抗体和DAPI实施检测。用Target Activation V2算法(Cellomics)分析p-组蛋白H3的细胞水平,以测定阳性细胞百分比。对于成像测定,用受影响的细胞对比DMSO对照的百分比计算浓度-反应曲线和相应的IC50和EC50值。
集落形成测定:用AMG 900、紫杉醇或AZD1152 (0.5、5、50纳摩尔/L)处理肿瘤细胞达48小时,用完全培养基洗涤2次,在无药物完全培养基中以每孔5000个细胞的密度重新将细胞铺板。让细胞生长直到DMSO对照孔汇合。用结晶紫染料(Sigma)对细胞染色,用蒸馏水洗涤,用数字扫描仪(Hewlett-Packard)成像。
≥ 4N DNA含量测定:用AMG 900、AZD1152、MK-0457或PHA-739358 (基于效力改变浓度范围)处理肿瘤细胞达24小时,如前所述进行细胞周期分析(仅DNA染色) (1)。在LSRII流式细胞仪上用BD FACS Diva软件分析细胞。用具有≥4N DNA含量的细胞对比DMSO对照的百分比计算浓度-反应曲线和相应EC50值。
P-gp和BCRP细胞表面染色:通过用FITC缀合的P-gp (BD Bioscience)或APC缀合的BCRP (Millipore)抗体在冰上染色活细胞达30分钟来测定P-gp (ABCB1)和BCRP (ABCG2)的细胞表面表达。用匹配的同种型抗体(BD Bioscience)作为对照,并用存活力染色7-氨基放线菌素D (BD Biosciences)来排除死细胞。在LSRII流式细胞仪上用BD FACS Diva软件分析细胞。
极光激酶基因分析:用标准核酸提取方法自冷冻的HCT116细胞沉淀(三种AZD1152-抗性细胞亚克隆和一种亲代细胞对照)分离总RNA和基因组DNA。用总RNA来产生cDNA (Advantage RT-PCR试剂盒, Clontech)。用扩增-聚合酶-长-模板(Expand-polymerase-long-template)试剂盒(Roche)实施全长aurora-A和-B基因转录物的PCR扩增。PCR引物对包括:aurora-A (GCTTGTTACTTATTACAGCTAGAGGCATCATG和TCAAGGATTTCTCCCCCTGCACGATTC)、aurora-B (TCTCCTCCCCCTTTCTCTCTAAGGATG和ACCCGAGTGAATGACAGGGACCATC)。利用基于5’和3’侧翼内含子的7个引物组((AACAGCCATCCAGAGGGTTCAGGAAG和CCACACACCCAGTCTGTTCTTCATCC)、(AAGGGGAGCATTGGCATCCCTGACTTTC和GTATTTGGGGAAAATGCTGGGCTCAGAC)、(ACCAGGCAGTGACGGTGGCATCATATG和TGACAGCCACAAACAGAGCTCCCAC)、(GGTAAGTGTTCCACCTCAGACGGAAATTG和CATTAAACTGGGTCATTCCTAACTGGTACTCAG)、(CTCAATGAAAGCTGGGGAAGGAGAATTTCC和AGAGGCATTGATAGTGGAAACCTCACATC)和(ACAGTGAGACTTACAGACGCATCCTCAAG和AGGAGAGCTCCCTGAACACACACAAAG)),用与上文所述同样的PCR试剂盒自基因组DNA扩增aurora-C的7个外显子。按照厂商推荐方案(Invitrogen)将PCR DNA产物亚克隆到pCR2.1载体。用侧翼载体引物对含有aurora-A、-B和-C基因产物的纯化的质粒进行双脱氧法循环测序。在3730xl DNA分析仪(Applied Biosystems)上进行测序反应,用Sequencher软件(Gene Codes Corporation)分析输出序列。
表6阐明AMG 900怎样对所有多重耐药肿瘤细胞系表现出一致的效力。
表6-A
注释:NCI-H460-PTX细胞系的来源为肺;MDA-MB-231-PTX细胞系为乳腺,MES-SA Dx5细胞系为子宫,RPMI-8226细胞来自多发性骨髓瘤。
用另外的细胞系进行了相似的实验,其如下表6-B所示。
表6-B
注释:ABC转运蛋白状态(* = P-gp+;** = P-gp-和/或BCRP+)
ND = 未确定的
实施例6
另外,体内针对适应在AZD1152这种选择性极光激酶B抑制剂存在下生长的HCT-116细胞评估了AMG 900。本实验亦对抵抗极光激酶抑制剂的可能备选机理带来一些曙光。因此,使HCT116细胞适应于在AZD1152存在下生长。然后在HCT116亲代和AZD1152-抗性细胞系中评估AMG 900的活性。
令人惊讶地发现AMG 900诱导多倍体,并抑制适应在AZD1152存在下生长的HCT116亚系的集落形成。与AZD1152的34和672纳摩尔/L相比,AMG 900的细胞≥ 4N DNA含量EC50值分别为2和5纳摩尔/L (图6-A)。AMG 900在两种HCT116细胞系中都在浓度≥ 5纳摩尔/L下抑制集落形成,而变体亚系对50纳摩尔/L的AZD1152不敏感(图6-B)。两种HCT116细胞系对紫杉醇同样敏感,其P-gp和BCRP表达为阴性(图6-C)。令人感兴趣的是,HCT116变体亚系在aurora-B基因的一个等位基因中荷有错义突变(TGG → TTG;W221L),而在aurora-A和-C基因中未检测到突变。这些结果提示AMG 900在抵抗AZD1152的肿瘤细胞、更具体地携带aurora-B杂合突变的肿瘤细胞中保持活性,所述杂合突变可能负责AZD1152抗性。因此,该意外阳性的数据表明MAG 900在治疗抵抗AZD1152的肿瘤细胞中保持有效性的令人惊讶的能力。
图6:AMG 900对HCT116亲代、AZD1152-抗性HCT116细胞系(图6-A)和紫杉醇抗性细胞系(图6-B)的作用
方法:
图6-A:用渐增浓度的AMG 900或AZD1152处理HCT116细胞系达24小时。用流式细胞术评估表示为DMSO处理对照百分比(POC)的≥ 4N DNA含量的细胞的累积。从两个独立实验测定浓度-反应曲线和计算EC50值(误差棒,±SD)。
图6-B:用HCT116细胞系(亲代和AZD1152-抗性)进行集落形成测定。用DMSO、AMG 900、AZD1152或紫杉醇以指定浓度处理细胞达48小时,并在缺乏抑制剂的完全培养基中重新铺板。在DMSO处理的细胞达到汇合后,用结晶紫染色细胞并成像(重复孔)。
图6-C:通过流式细胞术评估并分析了用藻红蛋白(PE)缀合的P-gp和别藻蓝蛋白(APC)缀合的BCRP抗体共同染色的HCT116细胞系(亲代和AZD1152-抗性)的细胞表面上P-gp和BCRP表达的程度。每一细胞系用同种型对照来确立背景荧光。将MES-SA-Dx5和RPMI 8226细胞系分别用作P-gp和BCRP表达的阳性对照。
动物
:
接收5-6周龄的雌性无胸腺裸小鼠(Harlan Sprague Dawley),安置在消毒笼中。随意提供反渗透水和高压灭菌的食物。在内部IACUC方案下实施所有动物研究,并满足所有AAALAC规范。
药效学测定(检测磷酸化组蛋白H3)
:
给予已建立人HCT 116或Colo 205异种移植物肿瘤的小鼠单次口服剂量的对照(只有溶媒)或指定剂量的AMG 900 (n=3只动物/组)。在3或6小时时,收集肿瘤、骨髓或皮肤组织用于药效学评估(p-组蛋白H3水平)。亦收集血浆用于药代动力学分析。
流式细胞术(FCM):让肿瘤解离到单细胞混悬液中,并在90%甲醇中于-20oC固定至少24小时。然后用抗p-组蛋白H3 (ser-10)和抗细胞角蛋白抗体染色细胞,并用碘化丙锭复染。在LSRII流式细胞仪上运行FACSDiva软件获得数据。评估细胞周期G2M期的骨髓和细胞角蛋白阳性肿瘤细胞的p-组蛋白H3。自溶媒治疗的小鼠收集肿瘤和骨髓细胞用作p-组蛋白H3基线对照。通过单向ANOVA分析测定统计学显著性。
激光扫描细胞术(LSC):用抗p-组蛋白H3抗体接着是alexa-633缀合的山羊抗兔IgG染色来自FFPE组织样品(皮肤和肿瘤)的一式三份切片。用包括DNA染料Hoechst33342的Prolong Gold antifade固定玻片。在LSC上用40x物镜(以0.5μ像素分辨率)捕获图像。基于限定的红色荧光阀值确定p-组蛋白H3事件的数目。只计数大于20 μm2的事件。将轮廓事件(Contoured event)重定位至图库以确证分割的准确性。将数据用SAS V9.3分析并应用Dunnett调整。在α = 0.05显著性水平下评估所有统计学检验。
细针抽吸(FNA):通过以预定和一致的模式(3x)通过肿瘤周围皮肤的小切口将25规针插入来收集肿瘤抽吸物,然后排出到2%多聚甲醛中。将细胞通过细胞离心涂片器涂片到显微镜载玻片上,用对EpCAM (上皮肿瘤标记,Alexa Fluor 488)和pHH3 (有丝分裂标记,Alexa Fluor 647)特异的抗体染色,并用DAPI (DNA含量)复染。用iCyte LSC (激光405 nm、488 nm、633 nm,PMT过滤器:450/40、530/30、650/LP)来捕获40x放大倍数的视野图像,并定量EpCAM、pHH3和DNA含量。通过将细胞图像重定位到图库中来确证群体的完整性。报告G2M中EpCAM、pHH3阳性细胞的数目。数据表示为平均值+/-平均标准误差(SEM)。用ANOVA接着Bonferroni Dunnett事后分析确定统计学显著性。
血浆中的AMG 900浓度(药代动力学测定):
通过加入溶剂混合物(含0.01%三氟乙酸的90%甲醇、10%水)提取血浆样品(50 μL)以分离分析物并沉淀血浆蛋白。用含0.1%甲酸的水(流动相A)和含0.1%甲酸的乙腈(流动相B)在Varian Pursuit PFP分析柱(2.0 x 30 mm, 5微米)上利用反相液相色谱法, 通过LC-MS/MS来测定提取的样品中的AMG 900浓度。
异种移植物模型:
用2 x 106个人HCT 116结肠肿瘤细胞皮下注射小鼠。当肿瘤已建立(大约200 mm3)时,将小鼠随机分为实验治疗组(n = 10),并在实验期间以每天1.5、2.25或3 mg/kg或间歇地3.75、7.5或15 mg/kg用AMG 900口服治疗。每日为小鼠提供营养补充品。每周用卡尺和分析型数字称分别记录肿瘤体积和体重两次。肿瘤数据表示为平均肿瘤体积+/- SEM。通过重复测量ANOVA (RMANOVA)接着Scheffe事后分析来确定肿瘤生长抑制的统计学显著性。
实施例7
在包括三种MDR异种移植物模型在内的来自5种不同肿瘤类型(乳腺、结肠、肺、胰腺和子宫)的人异种移植物组中,进一步评估AMG 900对肿瘤生长的体内作用。以15 mg/kg每天2次、每周连续2天达3周或以每天3 mg/kg每天2次达3周对荷有已建立的肿瘤的小鼠经口给予AMG 900。在下表7中报告每一异种移植物模型的最大肿瘤生长抑制(TGI)百分比。TGI百分比计算为在研究期间溶媒治疗的对照和AMG 900治疗的肿瘤体积的变化之间的差异。通过RMANOVA接着Scheffe或Dunnett事后检验来确定与媒溶治疗对照相比的肿瘤生长抑制的统计学显著性,其由星号指出(*P < 0.005, **P < 0.0005)。
与溶媒治疗的对照组相比,AMG 900在所有9种异种移植物模型中表现出显著的抗肿瘤活性(50-97%肿瘤生长抑制(TGI))。重要的是,AMG 900在MES-SA-Dx5 (84% TGI, P < 0.0001)和NCI-H460-PTX (66% TGI, P < 0.0001)异种移植物模型中有活性,这两种异种移植物模型抵抗以其各自的最大耐受剂量给予的多西他赛或紫杉醇。
因此,AMG 900在体内抑制多种人肿瘤异种移植物的生长,所述人肿瘤异种移植物包括多重耐药模型和护理标准的抗有丝分裂药物。具体而言,数据显示AMG 900令人惊讶地抑制aurora-B在HCT116肿瘤中的活性,并抑制代表多种肿瘤类型的多种异种移植物的生长。
表7
肿瘤模型 | 来源 | 最大TGI (%) |
MDA-MB-231 | 乳腺 | 82** |
COLO 205 | 结肠 | 73* |
HCT-15 (MDR) | 结肠 | 50* |
HCT116 | 结肠 | 85** |
NCI-H460 | 肺 | 85** |
NCI-H460-PTX (MDR) | 肺 | 65** |
MiaPaCa2 | 胰腺 | 60** |
MES-SA | 子宫 | 87** |
MES-SA-Dx5 (MDR) | 子宫 | 84** |
参考文献: Payton M, Chung G, Yakowec P,等. Discovery and evaluation of dual CDK1 and CDK2 inhibitors (双重CDK1和CDK2抑制剂的发现和评估). Cancer Res 2006;66:4299-4308。
适应症
肿瘤形成对极光激酶抑制剂的抗性的机理很可能对于不同物质不同。尽管更清楚地了解驱动癌症表型的分子力将提供分子靶向药物或疗法的基础,所述基础可开发给定疗法的可识别的遗传或外遗传易感性,但理解抵抗疗法的遗传基础亦是关键的。这种遗传理解可提供另外的过滤程序,利用该过滤程序将预期患者群分级。例如,已发表的遗传证据提示,目前正在进行临床评估的极光激酶抑制剂AZD1152和潜在地另一种临床化合物VX-680,在过表达MDR1或BCRP的肿瘤细胞中可能相对无效。在DNA修复缺陷型结肠癌系HCT116的选择期间出现的aurora B激酶结构域突变,可能导致抗性。发现这些催化结构域突变亦足以使细胞抵抗AZD1152和VX-680,这表明对这些药剂的抗性可独立于MDR发生。The Pharmacogenomics Journal, (2009) 9, 第90-102页。
本发明提供化合物AMG 900,其为极光激酶抑制剂,拥有治疗用传统护理标准化疗剂已经难治疗的癌症的能力,所述化疗剂包括抗有丝分裂剂,例如紫杉烷类(紫杉醇和多西他赛)和长春花生物碱。另外,AMG 900具有治疗抵抗其它极光激酶抑制剂的癌症的能力,所述其它极光激酶抑制剂包括但不限于AZD 1152、VX-680和PHA-739358。一般而言,所述肿瘤因用抗癌剂在先和/或长期治疗而发展出抗性。
因此,在本发明的一个实施方案中,提供治疗受试者的癌症的方法,所述方法包括给予受试者有效剂量的化合物N-(4-((3-(2-氨基-4-嘧啶基)-2-吡啶基)氧基)苯基)-4-(4-甲基-2-噻吩基)-1-酞嗪胺,其中受试者的癌症先前已用抗癌剂治疗。在另一实施方案中,抗癌剂为化疗剂。在另一实施方案中,化疗剂为抗有丝分裂剂或蒽环霉素。在再一实施方案中,化疗剂为选自以下的药剂:泰素、多西他赛、长春新碱、长春碱、长春地辛和长春瑞滨、柔红霉素、多柔比星、伊达比星、表柔比星和米托蒽醌。在再一实施方案中,抗癌剂为AZD1152、PHA-739358、MK-0457或其组合。
因此,可将AMG 900用于治疗细胞增殖病症,包括不受控制的细胞生长和异常细胞周期调控,其先前亦已用紫杉烷类护理标准疗法治疗。
为此,AMG 900可用于但不限于防止或治疗癌症,包括例如各种实体瘤和血液学来源的肿瘤,例如:癌,包括但不限于膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌(包括小细胞肺癌)、食管癌、胆囊癌、卵巢癌、胰腺癌、胃癌、子宫颈癌、甲状腺癌、前列腺癌、子宫癌和皮肤癌(包括鳞状细胞癌);淋巴谱系的造血系统肿瘤(包括白血病、急性淋巴细胞性白血病(acute lymphocitic leukemia)、急性成淋巴细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞性淋巴瘤和伯基特氏淋巴瘤(Burkett's lymphoma));骨髓谱系的造血系统肿瘤(包括急性和慢性髓细胞性白血病(AML和CML)、骨髓增生异常综合征和前髓细胞性白血病);间充质起源的肿瘤(包括纤维肉瘤和横纹肌肉瘤及其它肉瘤,例如软组织和骨);中枢和外周神经系统肿瘤(包括星形细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤);和其它肿瘤(包括黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病(xenoderoma pigmentosum)、角化棘皮瘤(keratoctanthoma)、甲状腺滤泡状癌(thyroid follicular cancer)和卡波西肉瘤),其中所述癌症已复发或变得难治疗的。亦可用AMG 900治疗抗癌症治疗例如用激素业已难治疗的癌症,例如前列腺癌、卵巢癌、肺癌、乳腺癌、胆管癌或其它类型癌症。
在一个实施方案中,本发明提供治疗受试者的一种或多种选自以下的癌症的方法:子宫癌、乳腺癌、肺癌(包括非小细胞肺癌)、结肠癌、前列腺癌、皮肤癌、肾癌、肝癌、白血病(包括前髓细胞性白血病、慢性髓细胞样白血病和T细胞白血病)、多发性骨髓瘤、卵巢癌和骨髓癌,所述方法包括给予受试者有效剂量的AMG 900,其中受试者的癌症先前业已用一种或多种选自以下的化疗剂治疗或变得难以用所述化疗剂治疗:多柔比星、柔红霉素、更生霉素、秋水仙碱、长春碱、长春新碱、紫杉醇、多西他赛、依托泊苷和米托蒽醌。在另一实施方案中,本发明提供治疗一种或多种选自以下的癌症的方法:膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌、非小细胞肺癌、头颈癌、食管癌、胃部癌症(gastric cancer)、卵巢癌、胰腺癌、胃癌、子宫颈癌、甲状腺癌和前列腺癌或淋巴瘤或白血病。AMG 900亦可用于治疗晚期实体瘤,包括但不限于膀胱肿瘤、乳腺肿瘤、结肠肿瘤、肾肿瘤、肝肿瘤、肺肿瘤、非小细胞肺肿瘤、头颈肿瘤、食管肿瘤、胃部肿瘤、卵巢肿瘤、胰腺肿瘤、胃肿瘤、子宫颈肿瘤、甲状腺肿瘤和前列腺肿瘤。
本发明亦提供用于治疗以下疾病的方法:实体瘤、肉瘤(尤其是尤因肉瘤和骨肉瘤)、视网膜母细胞瘤、横纹肌肉瘤、成神经细胞瘤、造血系统恶性(包括白血病和淋巴瘤)、肿瘤诱发的胸腔积液或心包积液和恶性腹水。
除可用于人治疗外,所述化合物亦可用于伴侣动物、外来动物和家畜(包括哺乳动物、啮齿动物等等)的兽医治疗。例如,可用AMG 900相似地治疗包括马、狗和猫在内的动物的用护理标准的癌症化疗治疗难治疗的癌症。
制剂
AMG 900可作为药物组合物给予癌症受试者,所述药物组合物包含与一种或多种无毒药学上可接受载体、稀释剂和/或辅助剂(本文统称为"赋形剂"材料)组合的化合物(其为本发明活性药物成分或API) N-(4-((3-(2-氨基-4-嘧啶基)-2-吡啶基)氧基)苯基)-4-(4-甲基-2-噻吩基)-1-酞嗪胺。可按照传统制药方法对AMG 900或其药学上可接受的盐形式进行加工,以产生用于给予患者(包括人和其它哺乳动物)的药物和药物组合物。
可通过任何合适途径将药物组合物给予受试者,可使药物组合物适于所述途径并以对预期的难治疗的癌症治疗有效的剂量给予。组合物或API可例如以含有常规药学上可接受载体、辅助剂和溶媒的剂量单位制剂,经口、粘膜、局部、直肠、肺部例如通过吸入喷雾或胃肠外给予,胃肠外包括血管内、静脉内、腹膜内、皮下、肌内、胸骨内和输注技术。
对于口服给药,药物组合物可呈例如片剂、胶囊剂、混悬剂或液体形式。药物组合物优选以含有特定量活性成分的剂量单位形式制备。所述剂量单位实例为片剂或胶囊剂。例如,这些可含有约1-2000 mg、通常约1-500 mg量的活性成分。用于人或其它哺乳动物的合适的每日剂量可视患者病况和其它因素而在很大程度上变化,但再次可用常规方法和实践来确定。
给予的API (AMG 900)的量和用于治疗难治疗的癌症病况的剂量方案视多种因素而定,所述因素包括受试者年龄、体重、性别和医疗条件、疾病类型、癌症严重程度、给药途径和给药频率和AMG 900或其特定形式(包括特定盐形式)的物理化学性质。因此,剂量方案可变化。合适的每日剂量可为约0.01-500 mg/kg体重,有利地在约0.01-约50 mg/kg体重之间,更有利地在约0.1-约30 mg/kg体重之间,甚至更有利地在约0.1 mg/kg体重-约25 mg/kg体重之间。在一个实施方案中,本发明提供治疗受试者的癌症的方法,所述方法包括给予受试者介于约0.5 mg/kg-约25 mg/kg范围的有效剂量的AMG 900或其药学上可接受的盐,其中受试者的癌症难以用抗有丝分裂剂进行的治疗来治疗。在另一实施方案中,本发明提供治疗受试者的癌症的方法,所述方法包括给予受试者介于约1.0 mg/kg-约20 mg/kg范围的有效剂量的AMG 900或其药学上可接受的盐,其中受试者的癌症难以用包括抗有丝分裂剂在内的护理标准的化疗剂进行的治疗来治疗。在再一实施方案中,本发明提供治疗受试者的癌症的方法,所述方法包括给予受试者介于约3.0 mg/kg-约15 mg/kg范围的有效剂量的AMG 900或其药学上可接受的盐,其中受试者的癌症难以用抗有丝分裂剂进行的治疗来治疗。可以以每天1-4个剂量来给予每日剂量。
为治疗目的,可让AMG 900与适合于指定给药途径的一种或多种辅助剂或“赋形剂”组合。若以每剂量基础来给予,可让AMG 900与以下物质混合形成最终制剂:乳糖、蔗糖、淀粉粉末、链烷酸的纤维素酯、纤维素烷基酯、滑石粉、硬脂酸、硬脂酸镁、氧化镁、磷酸和硫酸的钠盐及钙盐、明胶、阿拉伯橡胶、藻酸钠、聚乙烯吡咯烷酮和/或聚乙烯醇。例如,可将AMG 900和一种或多种赋形剂通过已知的公认方法压片或制成胶囊用于方便地给药。合适的制剂实例包括但不限于丸剂、片剂、软壳和硬壳凝胶胶囊、锭剂、经口可溶的形式和其迟释或控释的制剂。具体而言,胶囊或片剂制剂可含有一种或多种控释物质作为与一种或多种API的分散体,所述控释物质为例如羟基丙基甲基纤维素。
在银屑病和其它皮肤病况情况下,可优选将AMG 900的局部制剂每天2-4次施用于受影响的区域。适于局部给药的制剂包括适于渗透皮肤的液体或半液体制剂(例如擦剂、洗剂、软膏剂、乳膏剂、糊剂、混悬剂等等);适于给予眼睛、耳朵或鼻的滴剂。活性成分的合适局部剂量为每天1-4次、优选每天1或2次给予的0.1 mg-150 mg。对于局部给药,API可占制剂重量的0.001%-10% w/w,例如1%-2%,尽管其可占多至制剂的10% w/w,但优选不超过5% w/w,更优选0.1%-1%。
当在软膏剂中调配时,可将AMG 900与石蜡或水-混溶的软膏基质一起使用。或者,其可与水包油乳膏基质一起调配为乳膏剂。若需要,乳膏基质的水相可包括例如至少30% w/w的多元醇,例如丙二醇、丁烷-1,3-二醇、甘露醇、山梨醇、丙三醇、聚乙二醇及其混合物。局部制剂可期需包括促进活性成分经由皮肤或其它受影响区域吸收或渗透的化合物。所述皮肤渗透促进剂的实例包括DMSO和有关的类似物。
亦可通过透皮装置给予AMG 900。优选用贮库及多孔膜类型的药贴或固体基质种类的贴剂实现透皮给予。在任一种情况下,都自贮库或微胶囊通过膜连续递送AMG 900到活性剂可渗透的粘合剂,所述粘合剂与接受者的皮肤或粘膜接触。若通过皮肤吸收AMG 900,则将AMG 900的受控制且预定的流量给予接受者。在微胶囊情况下,包胶剂亦可作为膜起作用。
可自已知成分以已知方式来构成乳剂的油相。尽管油相可仅包含乳化剂,但其可包含至少一种乳化剂与脂肪或油或与脂肪及油二者的混合物。优选包括亲水乳化剂与作为稳定剂的亲脂乳化剂在一起。亦优选包括油和脂肪二者。总之,含或不含稳定剂的乳化剂 构成所谓的乳化蜡,乳化蜡又与油及脂肪一起构成所谓的乳化软膏基质,其形成乳膏制剂的油性分散相。适用于所述制剂的乳化剂和乳剂稳定剂包括例如:Tween 60、Span 80、十六醇十八醇混合物、肉豆蔻醇、单硬脂酸甘油酯、十二烷基硫酸钠、单独或与蜡一起的二硬脂酸甘油酯或本领域熟知的其它材料。
因为API在可能用于药物乳剂制剂的大部分油中的溶解度都非常低,所以制剂的合适油或脂肪的选择基于获得所期需的美容性质。因此,乳膏剂应该优选为不油腻、无着色的可洗产品,且具有避免从管或其它容器渗漏的合适的粘稠度。可使用直链或支链的一碱价或二碱价烷基酯,例如二异己二酸酯、硬脂酸异十六烷基酯、椰子脂肪酸的丙二醇二酯、肉豆蔻酸异丙酯、油酸癸酯、棕榈酸异丙酯、硬脂酸丁酯、棕榈酸2-乙基己酯或支链酯的混合物。这些可视所需性质单独或组合使用。或者,可使用高熔点脂质,例如白软石蜡和/或液体石蜡或其它矿物油。
适于局部给予眼睛的制剂亦包括滴眼剂,其中活性成分溶解于或悬浮于合适的载体,尤其是AMG 900的水性溶剂中。AMG 900优选以0.5-20%、有利地0.5-10%、尤其是约1.5% w/w的浓度存在于所述制剂中。
用于胃肠外给予的制剂可呈水性或非水性等渗无菌注射溶液剂或混悬剂形式。这些溶液剂和混悬剂可用对用于口服给药制剂提及的一种或多种载体或稀释剂或通过用其它合适的分散剂或湿润剂和助悬剂,自无菌粉末或颗粒制备。例如,可将AMG 900溶解于水、聚乙二醇、丙二醇、乙醇、玉米油、棉籽油、花生油、芝麻油、苯甲醇、氯化钠、西黄蓍胶和/或各种缓冲液。制药领域普遍地熟知其它辅助剂和给药方式。亦可作为与包括盐水、葡萄糖或水在内的合适载体或与环糊精(即Captisol)、共溶剂增溶(即丙二醇)或胶束增溶(即Tween 80)的组合物通过注射给予AMG 900。
无菌注射制剂亦可为无毒胃肠外可接受的稀释剂或溶剂中的无菌注射溶液剂或混悬剂,例如作为1,3-丁烷二醇中的溶液剂。在可采用的可接受的溶媒和溶剂中的有水、林格氏溶液和等渗氯化钠溶液。另外,常规采用无菌不挥发油作为溶剂或悬浮基质。为此目的,可采用任何温和的不挥发油,包括合成的甘油一酯或甘油二酯。另外,脂肪酸例如油酸可用于制备注射剂。
对于肺部给药,药物组合物以呈气雾剂的形式给予,或用包含干粉气雾剂的吸入器给予。
可通过让药物与合适的无刺激性的赋形剂混合来制备用于直肠给予药物的栓剂,所述赋形剂为例如可可油和聚乙二醇,其在常温下为固态但在直肠温度下为液态,因此将在直肠中熔化并释放药物。
可对药物组合物进行常规制药操作,例如灭菌,和/或药物组合物可含有常规辅助剂,例如防腐剂、稳定剂、湿润剂、乳化剂、缓冲剂等。片剂和丸剂可另外用肠溶衣制备。所述组合物亦可包含辅助剂,例如湿润剂、甜味剂、矫味剂和芳香剂。
联合
尽管AMG 900可作为单独的活性药剂给药或给予,但其亦可与一种或多种化疗剂和/或抗有丝分裂剂联合使用。当联合给予时,可将AMG 900调配为同时或在不同时间序贯给予的单独组合物,或可将AMG 900作为单一组合物给予。
在限定本发明AMG 900和其它化疗剂的应用时,短语"共同疗法"(或"联合疗法")意欲包括在提供药物组合的有益作用的方案中以序贯方式给予每一种药剂;还意欲包括以基本上同时的方式例如在具有固定比率的这些活性剂的单一胶囊中或在每一种药剂的多个单独胶囊中,共同给予这些药剂。
具体来说,在预防或治疗癌症中,AMG 900的给予可与本领域技术人员已知的其它化疗剂联合,所述其它化疗剂包括抗有丝分裂疗法。本发明不限制给药次序,即AMG 900可在给予已知抗癌剂或抗有丝分裂剂之前、与之同时或之后给予。
前述仅阐述本发明,并非意欲限制本发明至所揭示的用途。对本领域技术人员常规的修改和变化意欲落在本发明范围和性质内,本发明范围和性质在随附权利要求书中限定。所有提及的参考资料、专利、申请和出版物通过引用以其整体并入本文,如同书写于本文中一样。
Claims (14)
1.化合物N-(4-((3-(2-氨基-4-嘧啶基)-2-吡啶基)氧基)苯基)-4-(4-甲基-2-噻吩基)-1-酞嗪胺或其药学上可接受的盐用于在受试者中治疗癌症的用途,其中所述受试者的癌症难以用抗癌剂进行的治疗来治疗。
2.权利要求1的化合物的用途,其中所述抗癌剂为化疗剂。
3.权利要求2的化合物的用途,其中所述化疗剂为选自抗有丝分裂剂和蒽环霉素的化疗剂。
4.权利要求2的化合物的用途,其中所述化疗剂为选自以下的化疗剂:泰素、多西他赛、长春新碱、长春碱、长春地辛和长春瑞滨、柔红霉素、多柔比星、伊达比星、表柔比星和米托蒽醌。
5.权利要求1的化合物的用途,其中所述抗癌剂为AZD1152、PHA-739358、MK-0457或其组合。
6.权利要求1-5中任一项的用途,其中所述癌症为以下中的一种或多种:(a)实体瘤或血液学来源的肿瘤,其选自:膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌、小细胞肺癌、食管癌、胆囊癌、卵巢癌、胰腺癌、胃癌、子宫颈癌、甲状腺癌、前列腺癌和皮肤癌:(b)淋巴谱系的造血系统肿瘤,其选自:白血病、急性淋巴细胞性白血病、急性成淋巴细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞性淋巴瘤和伯基特氏淋巴瘤;(c)骨髓谱系的造血系统肿瘤,其选自:急性和慢性髓细胞性白血病、骨髓增生异常综合征和前髓细胞性白血病;(d)间充质起源的肿瘤,其选自:纤维肉瘤和横纹肌肉瘤;(e)中枢和外周神经系统肿瘤,其选自:星形细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤;或(f)黑素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角化棘皮瘤、甲状腺滤泡状癌或卡波西肉瘤。
7. 权利要求1-5中任一项的用途,其中所述癌症为一种或多种选自以下的实体瘤:膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌、非小细胞肺癌、头颈癌、食管癌、胃部癌症、卵巢癌、胰腺癌、胃癌、子宫颈癌、甲状腺癌和前列腺癌;或淋巴瘤或白血病。
8. 权利要求1-5中任一项的用途,其中所述癌症为前列腺癌、卵巢癌、乳腺癌、胆管癌、急性髓细胞样白血病、慢性髓细胞样白血病或其组合。
9.化合物N-(4-((3-(2-氨基-4-嘧啶基)-2-吡啶基)氧基)苯基)-4-(4-甲基-2-噻吩基)-1-酞嗪胺或其药学上可接受的盐在制备用于治疗难以用抗癌剂进行的治疗来治疗的癌症的药物中的用途。
10.权利要求9的化合物在制备用于治疗选自以下的癌症的药物中的用途:膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌、非小细胞肺癌、头颈癌、食管癌、胃部癌症、卵巢癌、胰腺癌、胃癌、子宫颈癌、甲状腺癌、前列腺癌、淋巴瘤、白血病、多发性骨髓瘤或其组合,其中所述癌症难以用抗癌剂进行的治疗来治疗。
11.权利要求9的化合物用于减小受试者的实体瘤大小的用途,其中所述受试者的肿瘤先前业已用选自紫杉醇、多西他赛、多柔比星和长春花生物碱的化疗剂治疗。
12.权利要求9的化合物的用途,其中所述抗癌剂为选自抗有丝分裂剂和蒽环霉素的化疗剂。
13.权利要求9的化合物的用途,其中所述抗癌剂为选自以下的化疗剂:泰素、多西他赛、长春新碱、长春碱、长春地辛和长春瑞滨、柔红霉素、多柔比星、伊达比星、表柔比星和米托蒽醌。
14.权利要求9的化合物的用途,其中所述抗癌剂为AZD1152、PHA-739358、MK-0457或其组合。
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CN103664737A (zh) * | 2012-09-25 | 2014-03-26 | 杨子娇 | 一类治疗房角狭窄的化合物及其用途 |
KR101701235B1 (ko) | 2013-09-30 | 2017-02-03 | 한국원자력의학원 | Hrp-3 억제제를 포함하는 방사선 또는 약물내성 암의 치료용 약학 조성물 |
WO2015070224A2 (en) | 2013-11-11 | 2015-05-14 | Amgen Inc. | Combination therapy including an mdm2 inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers |
CA2932560C (en) | 2013-12-03 | 2022-11-15 | Amgen Inc. | Crystalline forms of n-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine pharmaceutically acceptable salts and uses thereof |
JOP20190272A1 (ar) | 2017-05-22 | 2019-11-21 | Amgen Inc | مثبطات kras g12c وطرق لاستخدامها |
TWI731264B (zh) | 2017-09-08 | 2021-06-21 | 美商安進公司 | Kras g12c抑制劑以及其使用方法 |
JP7266043B2 (ja) | 2018-05-04 | 2023-04-27 | アムジエン・インコーポレーテツド | KRas G12C阻害剤及びそれを使用する方法 |
JP7377679B2 (ja) | 2018-11-19 | 2023-11-10 | アムジエン・インコーポレーテツド | がん治療のためのkrasg12c阻害剤及び1種以上の薬学的に活性な追加の薬剤を含む併用療法 |
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