CN104507479B - 通过联合治疗的半胱天冬酶‑3酶原激活 - Google Patents
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Abstract
本发明提供用于诱导细胞死亡例如癌细胞死亡的组合物和方法。公开了化合物的结合物以及相关的使用方法,包括化合物用于治疗癌症以及选择性诱导细胞凋亡的用途。与其他化合物以及化合物的结合物相比,所公开的药物结合物具有较低的神经毒性作用。
Description
相关申请
本申请要求依照35U.S.C.§119(e)于2012年3月6日提交的第61/607,098号美国临时专利申请的优先权,该临时专利申请通过引证方式纳入本申请。
背景技术
细胞凋亡或程序性细胞死亡在所有多细胞生物的发育和维持稳态过程中起着重要作用。癌症的常见标志是抵抗自然的细胞凋亡信号。根据癌症类型,这种抵抗通常是由于细胞凋亡级联反应中关键蛋白的上调或下调,或者是由于编码这些蛋白的基因中的突变。这些变化在内源性细胞凋亡途径和外源性细胞凋亡途径中均有发生,其中内源性凋亡途径通过线粒体和半胱天冬酶-9汇集,外源性凋亡途径涉及死亡受体与半胱天冬酶-8的作用。例如,已经在癌症中观察到了蛋白质——如p53、Bim、Bax、Apaf-1、FLIP和许多其他蛋白质——的适当水平的改变。这些改变可导致有缺陷的细胞凋亡级联反应,其中是上游的促细胞凋亡信号没有被充分地传递以激活执行者半胱天冬酶——半胱天冬酶-3和半胱天冬酶-7。
由于大多数细胞凋亡途径最终都涉及半胱天冬酶-3酶原的激活,上游的基因异常可有效地“打断”细胞凋亡线路,因此,这些细胞非典型地增殖。鉴于细胞凋亡在癌症中的重要作用,致力于开发靶向细胞凋亡级联反应中的特异蛋白质的治疗剂。例如,与级联成员诸如p53和Bcl家族中的蛋白质结合的肽或小分子结合剂,或者与细胞凋亡抑制剂(IAP)蛋白质家族结合的肽或小分子结合剂,具有促细胞凋亡活性,促进Apaf-1寡聚的化合物也同样具有促细胞凋亡活性。然而,因为这些化合物靶向细胞凋亡级联反应中的早期(或中间到高)位置,因此,具有影响这些成员的下游蛋白质的突变的癌症仍然可抵抗这些化合物的可能的有益效果。
对治疗目的有利的是识别直接激活细胞凋亡级联反应中远端下游(fardownstream)的促细胞凋亡蛋白质的小分子。这种方法可涉及级联反应中相当较低的位置,因此,使得甚至能够杀死那些具有影响上游细胞凋亡机器的突变的细胞。此外,如果促细胞凋亡蛋白质在癌细胞中被上调或者以增加的水平存在于癌细胞中,则这样的治疗策略会具有较高的成功可能性。因此,靶向细胞凋亡的下游效应物蛋白——半胱天冬酶-3酶原——的小分子的识别,将显著有助于目前的癌症治疗。
半胱天冬酶-3酶原到半胱天冬酶-3的转化或激活导致产生活性“执行者”半胱天冬酶形式,所述活性“执行者”半胱天冬酶形式随后催化众多蛋白底物的水解。活化的半胱天冬酶-3是异源二聚体的同源二聚体,并且是通过半胱天冬酶-3酶原的蛋白酶解产生的。在体内,这种蛋白酶解激活通常通过半胱天冬酶-8或半胱天冬酶-9的作用而发生。为确保酶原不被过早地激活,半胱天冬酶-3酶原具有12个氨基酸“保险栓(safety catch)”,其阻止进入蛋白酶解的ETD位点(氨基酸序列,ile-glu-thr-asp)。这种保险栓使得半胱天冬酶-3酶原能够抵抗自身催化激活和由半胱天冬酶-9导致的蛋白酶解。突变研究表明三个连续的天冬氨酸残基似乎是该保险栓的关键成分。保险栓的位置对pH敏感,因此,一旦发生细胞酸化(如在细胞凋亡过程中发生),保险栓被认为允许进入蛋白酶解的位点,活性半胱天冬酶-3可通过半胱天冬酶-9的作用或经由自身激活机制而产生。
在某些癌症中,半胱天冬酶-3酶原的水平相对于正常组织是提高的。对来自20位结肠癌患者的原代分离物(primary isolates)的研究显示,平均而言,相对于邻近的非癌性组织,半胱天冬酶-3酶原在这些分离物中被上调了六倍。此外,在某些神经母细胞瘤、淋巴瘤和肝癌中,半胱天冬酶-3酶原被上调。而且,在被国立癌症研究所(NCI)开发治疗项目(Developmental Therapeutics Program)用于癌症筛选的60个细胞系组(cell-linepanel)中进行了半胱天冬酶-3酶原水平的***性评估,这揭示了某些肺癌、黑素瘤、肾癌和乳腺癌显示显著升高的半胱天冬酶-3酶原表达水平。
由于活性半胱天冬酶-3在实现细胞凋亡中的作用,在某些癌性细胞类型中相对高水平的半胱天冬酶-3酶原以及令人感兴趣的保险栓-介导的半胱天冬酶-3酶原自身激活的抑制,直接修饰半胱天冬酶-3酶原的小分子可在靶向癌症治疗中具有很大应用。
联合治疗已经成为治疗癌症患者的标准。联合治疗药物鸡尾酒疗法的目的是在化学治疗剂之间实现协同或加和效果,借此有助于缩短治疗时间,降低毒性并增加患者存活率。作用于单一生化途径的药物对协同或增强作用而言是特别强有力的候选者,因为,它们可以模拟“合成致死”基因组合(″synthetic lethal″genetic combinations)。例如,聚(ADP-核糖)聚合酶-1(PARP-1)(一种促进DNA损伤修复的酶)的抑制剂,有效地与DNA损伤剂协同作用,如在细胞培养物、动物模型和人体临床试验中所证明的。然而,仍需要更加有效的疗法用于治疗多种形式的癌症,抗癌药物的新的协同组合将有助于该诉求。因此,需要识别新的细胞毒性剂,它们在杀死癌细胞方面是有效的,同时还保护正常宿主组织免受细胞毒性剂的不期望的毒性。
发明内容
本发明主要提供化合物、组合物以及治疗处理的方法。在多种实施方案中,本发明适用于多种癌症疾病和癌细胞类型,如乳腺癌、淋巴瘤、肾癌、黑素瘤、白血病、神经细胞瘤、肺癌、脑癌和本领域已知的其他癌症。本文尤其公开了包括能够诱导细胞死亡的小分子的组合物和方法。在一些实施方案中,所述组合物和方法涉及可直接或间接与程序性细胞死亡途径成员如半胱天冬酶-3酶原相互作用的化合物。在某些实施方案中,与直接或间接与程序性细胞死亡途径成员如半胱天冬酶-3酶原相互作用的其他化合物相比,所述组合物和方法具有降低的神经毒性。
联合抗癌治疗可由靶向不同生化途径的药物组成,或者由那些在相同途径中攻击不同靶标的化合物组成,模拟“合成致死”的基因组合。半胱天冬酶-3酶原激活剂PAC-1和第二活性剂的结合物对于诱导癌细胞的细胞凋亡性死亡已经显示出相当大的协同作用,经常达到完全超过加和效果的程度。PAC-1和第二活性剂的结合物可用于有效降低肿瘤模型中的肿瘤负荷,其中单独的化合物具有极小的效果或没有效果。本文中描述的数据显示了PAC-1/第二活性剂结合物用于治疗癌症的效力,更广义而言,显示出结合物可协同作用并提供显著加强的治疗益处。
因此,本发明提供一种组合物,其包含:
(a)化合物PAC-1:
(b)第二活性剂;和(c)药学上可接受的稀释剂、赋形剂或载体。所述第二活性剂可以是,例如,依托泊苷、硼替佐米、十字孢碱、多柔比星、他莫昔芬、顺铂、卡铂、紫杉醇,或另一种化学治疗剂,或本文描述的另外的活性剂。所述载体可包括水和用于有利地递送活性物质的任选组分如缓冲剂、糖、增溶剂(如环糊精),或它们的多种组合。在一个实施方案中,所述环糊精是2-羟丙基-β-环糊精。
PAC-1的浓度可以为约0.2μM至约5mM,或约2μM至约50μM,通常为约2.5μM、约5μM、约7.5μM、约10μM、约12.5μM、约15μM、约20μM、约25μM、约30μM、约40μM或约50μM,或介于任何前述数值之间的范围。所述第二活性剂的浓度可以为约1nM至约1mM,或约25nM至约1mM,通常为约1nM、约2nM、约3nM、约5nM、约10nM、约25nM、约50nM、约100nM、约250nM、约500nM、约750nM、约900nM、约1μM、约2.5μM、约5μM、约7.5μM、约10μM、约12.5μM、约15μM、约20μM、约25μM、约30μM、约40μM、约50μM、约75μM、约100μM、约125μM、约150μM、约200μM、约250μM、约300μM、约500μM、约750μM,或约1mM,或介于任何前述数值之间的范围。
在一个实施方案中,所述第二活性剂可以为依托泊苷,并且依托泊苷的浓度可以为约0.2μM至约50μM。
在另一实施方案中,所述第二活性剂可以为硼替佐米,并且硼替佐米的浓度可以为约50nM至约20μM。
在另一实施方案中,所述第二活性剂可以为十字孢碱,并且十字孢碱的浓度可以为约25nM至约200nM。
在另一实施方案中,所述第二活性剂可以为多柔比星,并且多柔比星的浓度可以为约50nM至约5μM。
在另一实施方案中,所述第二活性剂可以为他莫昔芬,并且他莫昔芬的浓度可以为约5μM至约50μM。
在另一实施方案中,所述第二活性剂可以为顺铂,并且顺铂的浓度可以为约5μM至约150μM。
在另一实施方案中,所述第二活性剂可以为卡铂,并且卡铂的浓度可以为约5μM至约150μM。
在另一实施方案中,所述第二活性剂可以为紫杉醇,并且紫杉醇的浓度可以为约0.5nM至约15nM。
本发明还提供抑制癌细胞生长或增殖的方法,包括使癌细胞与有效量的本文描述的组合物接触,从而抑制癌细胞的生长或增殖。在一些实施方案中,所述癌细胞可以是淋巴瘤细胞、骨肉瘤细胞、乳腺癌细胞或卵巢癌细胞。在另一实施方案中,所述癌细胞是下文中描述的另一细胞类型。
本发明进一步提供在癌细胞中诱导细胞凋亡的方法,包括使癌细胞与有效量的化合物PAC-1和有效量的第二活性剂接触,
从而在癌细胞中诱导细胞凋亡。在一些实施方案中,所述第二活性剂是依托泊苷、硼替佐米、十字孢碱、多柔比星、他莫昔芬、顺铂、卡铂或紫杉醇。在其他实施方案中,所述第二活性剂是下文中描述的活性剂。所述接触可以是在体外或者在体内。所述癌细胞可同时与PAC-1和第二活性剂接触。或者,在癌细胞与第二活性剂接触之前,所述癌细胞可与PAC-1接触,或者在癌细胞与第二活性剂接触之后,所述癌细胞可与PAC-1接触。
本发明更进一步提供在有需要的患者中治疗癌症的方法,包括同时或相继地给予患者治疗有效量的化合物PAC-1和有效量的第二活性剂,
从而治疗癌症。在一些实施方案中,所述第二活性剂是依托泊苷、硼替佐米、十字孢碱、多柔比星、他莫昔芬、顺铂、卡铂或紫杉醇。在其他实施方案中,所述第二活性剂是下文中描述的活性剂。化合物PAC-1和第二活性剂可同时给药。或者,化合物PAC-1和第二活性剂可相继地给药。在一个实施方案中,化合物PAC-1在第二活性剂之前给药。在另一实施方案中,化合物PAC-1可在第二活性剂之后给药。所述癌症可以是,例如,淋巴瘤、骨肉瘤、乳腺癌、卵巢癌或本文描述的另一癌症类型。
因此,本发明提供本文描述的组合物用于医药治疗中的用途。所述医药治疗可以是治疗癌症,所述癌症例如淋巴瘤、乳腺癌、肺癌、卵巢癌、胰腺癌、***癌、结肠癌以及本文描述的其他癌症。本发明还提供本文描述的组合物用于制备药物以治疗哺乳动物的疾病(例如人类的癌症)的用途。因此,本发明提供本文描述的化合物用于制备用于治疗哺乳动物(例如人类)的癌症的药物的用途。所述药物可包含药学上可接受的稀释剂、赋形剂或载体。
附图说明
下面的附图构成本说明书的一部分,它们用来进一步证明本发明的某些实施方案或多个方面。在某些情况下,可通过参考随附的附图结合在此给出的详细说明来最好地理解本发明的实施方案。本说明书和随附的附图可能强调某一具体实例,或本发明的某一方面。然而,本领域技术人员将理解的是所述实例或方面的部分可与本发明的其他实例或方面结合使用。
图1.结构不同的化学治疗剂的化学结构:PAC-1、SPAC-1、依托泊苷、多柔比星、硼替佐米、十字孢碱和他莫昔芬。
图2.PAC-1与依托泊苷对U-937(淋巴瘤)细胞死亡的作用。虚线代表纯粹加和效果的水平。图例如下对应柱形图中各柱:左侧柱=0μM依托泊苷,中间柱=2.5μM依托泊苷,右侧柱=5μM依托泊苷。
图3.PAC-1与万珂(硼替佐米)对U-937(淋巴瘤)细胞死亡的作用。对0nM硼替佐米而言,在0μM PAC-1下未观察到细胞死亡。在硼替佐米中6小时后测量到细胞死亡。虚线代表纯粹加和效果的预期水平,因此结合物在治疗相关的浓度下显示协同作用。
图4.PAC-1与十字孢碱对U-937(淋巴瘤)细胞死亡的作用。对0nM硼替佐米而言,在0-15μM PAC-1下观察到少量的细胞死亡或没有观察到细胞死亡。在十字孢碱中8小时后测量到细胞死亡。虚线代表纯粹加和效果的预期水平,因此结合物在治疗相关的浓度下显示协同作用。
图5.PAC-1与多柔比星协同杀死骨肉瘤143B(人OS)细胞。图例对应柱形图中各柱,其中顶部的图例条目对应于最左侧的柱,其余图例条目对应于其余柱,从顶部到底部分别对应于从左侧到右侧。在0nM多柔比星与0μM PAC-1下未观察到细胞死亡。虚线代表纯粹加和效果的水平,因此结合物在治疗相关的浓度下显示协同作用。
图6.PAC-1增强他莫昔芬在BT20(三阴性乳腺癌)细胞中的作用,在不同的PAC-1和他莫昔芬浓度下在36小时时评估。
图7.PAC-1和他莫昔芬的结合物协同杀死BT20(三阴性乳腺癌)细胞,在不同的PAC-1和他莫昔芬浓度下在24小时时评估。图例对应柱形图中各柱,其中顶部的图例条目对应于最左侧的柱,其余图例条目对应于其余柱,从顶部到底部分别对应于从左侧到右侧。
图8.PAC-1和他莫昔芬的结合物协同杀死MDA MB 436(三阴性乳腺癌)细胞,在不同的PAC-1和他莫昔芬浓度下在24小时时评估。图例对应柱形图中各柱,其中顶部的图例条目对应于最左侧的柱,其余图例条目对应于其余柱,从顶部到底部分别对应于从左侧到右侧。
图9.PAC-1和顺铂的结合物协同杀死IGROV-1(卵巢癌)细胞,在不同的PAC-1和顺铂浓度下在40小时时评估(膜联蛋白V/PI染色)。图例对应柱形图中各柱,其中顶部的图例条目对应于最左侧的柱(在0μM顺铂时不存在),其余图例条目对应于其余柱,从顶部到底部分别对应于从左侧到右侧。
图10.PAC-1和紫杉醇的结合物协同杀死IGROV-1(卵巢癌)细胞,在不同的PAC-1和紫杉醇浓度下在40小时时评估(膜联蛋白V/PI染色)。图例对应柱形图中各柱,其中顶部的图例条目对应于最左侧的柱(在0μM紫杉醇时不存在),其余图例条目对应于其余柱,从顶部到底部分别对应于从左侧到右侧。
图11.PAC-1与卡铂协同诱导培养的HOS(人骨肉瘤)细胞的死亡。细胞共处理8小时,更换培养基并使集落生长7天。
图12.PAC-1与卡铂协同诱导培养的143B(人骨肉瘤)细胞的死亡。细胞共处理8小时,更换培养基并使集落生长7天。
具体实施方式
作为进一步的介绍,已经发现了能够激活酶的化合物,所述酶在癌细胞中常常是过表达的或以增加的水平存在。所述化合物可在癌细胞中诱导程序性细胞死亡(细胞凋亡),包括在那些具有上调的或增加水平的半胱天冬酶-3酶原的癌细胞中。许多癌症抵抗标准的化学疗法。本文所描述的联合治疗利用半胱天冬酶-1酶原经由PAC-1的激活,PAC-1可与第二活性剂的化学治疗性质产生协同作用,以在活性剂之一单独可能较低效或完全无效的条件下提供效力。这些化合物也可在靶向癌症治疗中是成功的,其中可能在杀死癌细胞的选择性上有优势,而对含有低水平的半胱天冬酶-3酶原的非癌细胞具有相对降低的不良反应。这些不良反应可包括毒性,特别是神经毒性。
本文描述的化合物的结合物、组合物和方法可经由调控细胞凋亡或程序性细胞死亡以及在癌细胞的治疗中有效的其他化学治疗机制而起作用。在一个实施方案中,细胞凋亡的调控是通过诱导或激活细胞凋亡进行。在不同的实施方案中,化合物的给药可以是同时的或相继的。
因此,本发明提供通过PAC-1增强活性剂的方法,例如,用于治疗淋巴瘤、骨肉瘤或乳腺癌。在细胞凋亡过程中,酶原半胱天冬酶-3酶原经由蛋白酶解被激活为半胱天冬酶-3,然后,该活性半胱天冬酶-3裂解很多细胞基质,执行细胞凋亡程序。因为半胱天冬酶-3酶原蛋白水平在不同的肿瘤组织学中被提高,所以药物介导的半胱天冬酶-3酶原的直接激活作为选择性的抗肿瘤策略可为高度有效的。
某些化合物可增强半胱天冬酶-3酶原的活性和自身成熟,并在癌细胞中诱导细胞凋亡。半胱天冬酶酶原激活化合物-1(PAC-1,图1)经由抑制性锌离子的螯合作用而增强半胱天冬酶-3酶原的活性,在培养的癌细胞中诱导细胞凋亡,并且在多个鼠肿瘤模型中具有效力。已经发现PAC-1与数种治疗剂的新的结合物在治疗癌细胞中是协同有效的,所述癌细胞特别是本文所描述的淋巴瘤、骨肉瘤和乳腺癌细胞。因为PAC-1在细胞凋亡级联反应的后期起作用,所以它能够独特地与广泛的化学治疗活性剂协同作用,如下面所描述的。
定义
如本文中所使用的,所引用的术语具有以下含义。本说明书使用的所有其他术语和短语具有如本领域技术人员会理解的其普通含义。所述普通含义可通过参考技术词典获得,如Hawley’s Condensed Chemical Dictionary第14版,R.J.Lewis,John Wiley &Sons,New York,N.Y.,2001。
说明书中提到的“一个实施方案”、“实施方案”等,表示所述的实施方案可包括具体的方面、特征、结构、部分或特性,但不是每个实施方案必须包括所述方面、特征、结构、部分或特性。而且,这样的短语可以,但是不是必须,指的是本说明书中其他部分提及的相同实施方案。而且,当与一个实施方案一起描述具体的方面、特征、结构、部分或特性时,不管是否明确描述,本领域的技术人员会知晓所述方面、特征、结构、部分或特性影响其他实施方案或与其他实施方案相联系。
除非上下文中另有明确说明,单数形式“一个”(“a”,“an”)和“所述”(“the”)包括复数指代对象。因此,例如,提到“化合物”包括多个这种化合物,使化合物X包括多个化合物X。还要注意,可起草权利要求以排除任何任选要素。因此,本声明旨在充当使用排他性术语的先行基础,如“单独地”、“仅”等等,与权利要求要素的列举或“否定性”限定的使用有关。
术语“和/或”意指与该术语相关的所述项中的任何一项、所述项的任何组合、或所述项的所有项。短语“一个或多个”是本领域普通技术人员很容易理解的,尤其是在其使用的上下文中读到时。例如,苯环上的一个或多个取代基是指一到五个、或一到四个,例如如果该苯环被双取代。
术语“约”可指具体指明的数值的±5%、±10%、±20%、或±25%的变化。例如,“约50”百分比在一些实施方案中可具有45到55百分比的变化。对于整数范围,术语“约”可包括比在所述范围两端所列举的整数多和/或少一个或两个整数。除非本文另有说明,术语“约”旨在包括接近所述范围的数值(例如重量百分比),所述数值就单独成分、组合物或实施方案的功能而言是等价的。
技术人员会理解,所有的数目,包括那些表示成分、特性如分子量、反应条件等的量,都是近似值并且理解为在所有情况下任选被术语“约”修饰。这些值可取决于本领域的普通技术人员利用本说明书的教导而得到的所寻求的所需特性而不同。还可以理解,这样的数值固有地包含由它们各自的测试测量中存在的标准偏差所必然造成的变量。
本领域技术人员会理解,出于任何和所有目的,特别是在提供书面说明方面,本文所述的所有范围还包含任何和所有的可能的子范围和其子范围的组合,以及组成所述范围的单个数值,尤其是整数值。列举的范围(例如重量百分比或碳基团),包括所述范围内各个具体的数值、整数、小数或恒等式。任何列出的范围可容易地被认为充分说明并使得同一范围能被分解为至少两等份、三等份、四等份、五等份或十等份。作为非限制性实例,本文所述的每个范围可被轻易地分解为下三分之一、中三分之一和上三分之一等。本领域技术人员还会理解,所有的语言如“最高达”、“至少”、“大于”、“小于”、“多于”、“或更多”等都包括列举的数字并且所述术语是指随后可被分解为如上所述的子范围的范围。以同样的方式,本文列举的所有比例也包括落在更宽比例中的所有子比例。因此,对于基团、取代基和范围所列举的具体数值仅用于说明;它们不排除其他限定的数值或对于基团和取代基所限定的范围内的其他数值。
本领域普通技术人员还会很容易地理解,以常用的方式将成员分组在一起,如马库氏(Markush)基团,本发明不仅包含作为整体列举的整个组,还独立地包含组的每个成员和主要组的所有可能的亚组。另外,出于所有目的,本发明不仅包含主要组,还包含缺少一个或多个组成员的主要组。因此本发明设想明确排除所述组的任何一个或多个成员。因此,限制性条件可以用于所公开的类别或实施方案中的任何一个,由此,可将所列举的要素、种类、或实施方案中的任何一个或多个从所述类别或实施方案中排除(例如,如在明确的否定限制中使用的)。
术语“接触”是指接触、使接触、或使其非常或极为接近的行为,包括在细胞或分子水平上,例如,在溶液中、在反应混合物中、在体外、或在体内引起生理反应、化学反应、或物理变化。
“同时”意指(1)时间上同时地,或(2)在常见治疗方案过程中的不同时间。
“相继”是指给予所述方法中使用的一种活性剂后给予另一种活性剂。在给予一种活性剂后,可在第一种之后立刻给予下一种活性剂,或者可在给予第一种活性剂后的有效时间段之后给予下一种活性剂;有效时间段是用于从第一种活性剂给予中实现最大效益而给出的时间量。
“有效量”是指治疗疾病、障碍和/或病症,或带来所述效果(如激活或抑制)的有效量。例如,有效量可以是降低正被治疗的病症或症状的进展或严重性的有效量。确定治疗有效量在本领域技术人员的能力范围之内。术语“有效量”旨在包括本文所述化合物的量,或本文所述化合物的结合物的量,例如,在宿主中治疗或预防疾病或障碍,或治疗疾病或障碍的症状的有效量。因此,“有效量”一般意指提供了所需效应的量。在一个实施方案中,有效量是指本文所述的活性剂在单独或与药物载体结合时以单剂量或多剂量给药至细胞或受试者(例如患者)时抑制生长或增殖、诱导杀死、或预防过度增殖性细胞的生长的有效量。这种生长抑制或杀死可以表现为受试者存活的延长(例如患者的存活超出无此治疗时所预期的),或相对于无此治疗时受试者预后的任何改善。
术语“治疗”包括(i)预防疾病、病理学或医学病症的发生(例如,预防);(ii)抑制疾病、病理学或医学病症或阻止其发展;(iii)缓解疾病、病理学或医学病症;和/或(iv)减少与疾病、病理学或医学病症相关的症状。因此,术语“治疗”可延伸到预防,可包括预防、降低、阻止或逆转正被治疗的病症或症状的进展或严重性。因此,如果合适,术语“治疗”可包括医用的、治疗的、和/或预防的给药。在一些实施方案中,术语“处理”可指(i)预防肿瘤生长或肿瘤再生(预防),(ii)减少或消除目感兴趣的疾病或症状(治疗)或(iii)消除或破坏肿瘤(治愈)。
术语“抑制”是指减缓、停止或逆转疾病、感染、病症或细胞群的生长或进展。例如,与无治疗或接触时发生的生长或进展相比,所述抑制可大于约20%、40%、60%、80%、90%、95%或99%。此外,术语“诱导”、“抑制”、“增强”、“提高”、“增加”、“降低”等表示两种状态间的定量差异,并且可指两种状态之间的至少统计学上显著的差异。例如,“有效抑制过度增殖性细胞的生长的量”意指在一些实施方案中,细胞的生长速度可至少在统计学上显著不同于未处理的细胞。例如,这些术语在本文可被应用于例如增殖的速率。
短语“抑制过度增殖性细胞(例如肿瘤细胞)的生长或增殖”,是指减缓、中断、阻止或终止该细胞的生长和转移,并且不一定表示完全消除肿瘤生长。
术语“癌症”通常是指由异常细胞不受控制的生长所引起的一组超过100种疾病中的任意一种。癌症可采取实体瘤和淋巴瘤,和非实体癌症如白血病的形式。与复制直到成熟然后只在需要时才取代受损细胞的正常细胞不一样,癌细胞可无休止地生长和***,排挤附近的细胞并且最终扩散到身体的其他部分。
本发明提供了治疗癌症和癌性病症的方法。术语“癌性病症”涉及其中细胞处于异常状态的任何病症或由快速增殖或肿瘤形成所表征的病症。癌性病症在本质上可以是恶性的或非恶性的(例如癌前病症)。为了进一步描述“癌性病症”,可使用术语“过度增殖的”、“增生的”、“增生”、“恶性的”、“肿瘤的”和“肿瘤形成”。这些术语可互换使用并意指包括所有类型的过度增殖性生长、增生生长、癌性生长或致癌过程、肿瘤转移组织或恶性转化的细胞、组织或器官,而不考虑组织病理学的类型、浸润的阶段、或癌性测定(例如恶性的和非恶性的)。
术语“肿瘤形成”是指导致对正常生长控制丧失响应性的新的细胞生长,如肿瘤细胞生长。“增生”是指经历异常高的生长速率的的细胞。然而,这些术语可互换使用,如它们的内容所揭示的,通常是指正在经历异常的细胞生长速率的细胞。“肿瘤形成”和“增生”包括肿瘤,所述肿瘤可能是良性的、癌变前的、原位癌、恶性的、实体的或非实体的。在本发明范围内的一些癌性病症的实例包括,但不限于,***癌、转移性细胞膀胱癌、骨癌、乳腺癌、***、结肠直肠癌、胃癌、头颈癌、卡波西肉瘤、白血病、肺癌如原发性支气管肺癌、小细胞肺癌、和非小细胞肺癌、霍杰金淋巴瘤、非霍杰金淋巴瘤、恶性淋巴瘤、成神经细胞瘤、成骨癌(如骨的癌症)、眼癌(如视网膜母细胞瘤和眼的其他癌症)、卵巢癌、***癌、肾癌、皮肤癌如黑素瘤、软组织肉瘤、甲状腺癌和维尔姆斯肿瘤。在本发明范围内的非恶性过度增殖性病症的其他实例包括,但不限于,腺瘤、软骨瘤、内生软骨瘤、纤维瘤、肌瘤、粘液瘤、神经鞘瘤、成骨细胞瘤、成骨软骨细胞瘤、骨瘤、***状瘤等。
术语“白血病”或“白血病性癌症”是指造血和免疫***(血液和淋巴***)的所有癌症或肿瘤形成。这些术语是指成血器官的进行性的、恶性疾病,以血液和骨髓中的白细胞及其前体的异常增殖和发育为标志。骨髓瘤是指其他类型的血液和骨髓细胞的肿瘤。淋巴瘤是指淋巴组织的肿瘤。白血病的实例包括急性骨髓性白血病(AML)、急性成淋巴细胞性白血病(ALL)和慢性髓细胞性白血病(CML)。
如本文所描述的,本发明的组合物和方法可用于治疗或预防多种肿瘤形成疾病,包括如下病症:如,肢端着色斑性黑素瘤、光化性角化病、腺癌、腺样囊性癌、腺瘤、腺肉瘤、腺鳞状癌、星形细胞肿瘤、***癌、基底细胞癌、支气管腺癌、毛细管癌、类癌、癌、癌肉瘤、海绵状癌、胆管上皮癌、软骨肉瘤(chondosarcoma)、脉络丛***状瘤/癌、透明细胞癌、囊腺瘤、内胚层窦瘤、子宫内膜超常增生、子宫内膜间质肉瘤、子宫内膜样腺癌、室管膜癌、类上皮癌、尤因肉瘤、羽层状癌(fibrolamellar)、局灶性结节状增生(focal nodularhyperplasia)、胃泌素瘤、生殖细胞肿瘤、胶质母细胞瘤、胰高血糖素瘤、成血管细胞瘤(hemangiblastomas)、血管内皮瘤、血管瘤、肝腺瘤(hepatic adenoma)、肝腺瘤病(hepaticadenomatosis)、肝细胞癌、胰岛素瘤、上皮内肿瘤(intaepithelial neoplasia)、上皮间鳞状细胞肿瘤(interepithelial squamous cell neoplasia)、浸润型鳞状细胞肿瘤、大细胞癌、平滑肌肉瘤、恶性小痣、恶性黑素瘤、恶性间皮瘤(malignant mesothelial tumors)、髓母细胞瘤、髓上皮瘤、黑素瘤、脑膜癌、间皮癌、转移癌、粘液表皮样癌、神经母细胞瘤、神经上皮腺癌结节性黑素瘤、燕麦细胞癌、少突胶质细胞、骨肉瘤、胰多肽瘤、***状浆液性腺癌、松果体细胞瘤、垂体瘤、浆细胞瘤、假性肉瘤、肺胚细胞瘤、肾细胞癌、视网膜母细胞瘤、横纹肌肉瘤、肉瘤、浆液性癌、小细胞癌、软组织癌、生长抑素分泌肿瘤、鳞状癌、鳞状细胞癌、间皮下(submesothelial)、浅表扩散性黑素瘤、未分化癌、眼色素层黑素瘤(uvealmelanoma)、疣状癌、胰腺瘤、分化良好的癌以及维尔姆斯肿瘤。因此,本文所描述的组合物和方法可用于治疗膀胱癌、脑癌(包括颅内肿瘤诸如神经胶质瘤、脑膜瘤(meninigioma)、神经鞘瘤和腺瘤)、乳腺癌、结肠癌、肺癌(SCLC或NSCLC)、卵巢癌、胰腺癌和***癌。
在一些实施方案中,PAC-1和第二活性剂(例如,本文所述的化学治疗剂)的结合物对于治疗脑的癌症是特别有效的。脑的癌症包括,但不限于,少突神经胶质瘤和胶质母细胞瘤,包括多形性胶质母细胞瘤(GBM)。被癌性细胞侵袭的组织可位于脑本身(例如,颅或中央椎管)或在淋巴组织中、在血管中、在颅神经中、在脑外膜(脑脊膜)、头盖骨、垂体或松果腺中。可被治疗的脑癌的具体形式包括星形细胞瘤、软骨瘤、软骨肉瘤、脊索瘤、CNS(中枢神经***)淋巴瘤、颅咽管瘤、室管膜瘤、神经节神经胶质瘤、神经节瘤(也称作神经节细胞瘤)、神经胶质瘤包括星形细胞瘤、少突神经胶质瘤和室管膜瘤,血管母细胞瘤(也称作脉管肿瘤)、原始神经外胚瘤(PNET)如髓母细胞瘤、脑膜瘤和前庭神经鞘瘤(以前称作听神经瘤/神经鞘瘤)。
所述结合物还可用于治疗由源于身体其他器官的癌症侵入颅内球的转移性肿瘤。这些病症通常称为继发性脑肿瘤。可采用PAC-1和第二活性剂的结合物治疗的继发性脑肿瘤包括源于肺癌、乳腺癌、恶性黑素瘤、肾癌、结肠癌和其他癌症的脑转移瘤。
本发明范围内的癌性病症的其他实例包括,但不限于,神经母细胞瘤和成骨癌(例如,骨的癌症或骨组织的肿瘤生长)。可采用PAC-1和第二活性剂的结合物治疗的恶性原发性骨肿瘤的实例包括骨肉瘤、软骨肉瘤、尤因瘤、纤维肉瘤等,以及继发性骨肿瘤如已从其他器官扩散的转移病灶,包括乳腺癌、肺癌和***癌。
治疗剂和活性
半胱天冬酶酶原激活化合物-1(PAC-1,(2-(4-苄基哌嗪-1-基)-N-[(2-羟基-3-丙-2-烯基-苯基)亚甲基氨基]乙酰胺)在癌性细胞中选择性诱导细胞凋亡。PAC-1的结构如图1所示,制备PAC-1的方法描述于美国专利公开号2012/0040995(Hergenrother等人)中。
PAC-1经由抑制性锌离子的螯合作用而增强半胱天冬酶-3酶原的活性,并在癌细胞中诱导细胞凋亡。PAC-1可增强半胱天冬酶-3酶原的活性和自身成熟,并在癌细胞中诱导细胞凋亡。PAC-1还增强数种其他药物的化学治疗活性,通常其中单独的PAC-1或第二活性剂较低效或完全无效。因此,令人惊讶地是,已发现PAC-1与众多类型的化学治疗剂的活性起协同作用。可与PAC-1协同作用的化合物的类型的实例包括:
(a)bcl-2家族抑制剂/调节剂(包括bax和bcl-xl抑制剂);
(b)含BIR基序的蛋白质的调节剂(例如,存活素、SMAC模拟物等);
(c)微管或细胞骨架元素的调节剂/稳定剂或抑制剂(例如,紫杉烷类,如紫杉醇和多西他赛);
(d)烷化剂如环磷酰胺、DTIC或细胞毒性抗生素如多柔比星;
(e)DNA嵌入剂(例如铂类如顺铂、卡铂或奥沙利铂);
(f)自噬调节剂如替莫唑胺;
(g)肿瘤细胞信号传导抑制剂(例如,抑制剂或野生型或突变体EGFRs、braf、Ras、AKT、cMET、mTOR、PI3K、BTK、JAK/STAT家族成员,MEK);
(h)信号传导受体的抑制剂/调节剂(例如他莫昔芬,抗EGFRs、CD20、CD19以及肿瘤细胞中过表达或常规表达的其他受体的抗体);
(i)血管生成的抑制剂/调节剂(例如,VEGFs、VEGFRs、血管生成素、血管生成抑制素(angiostatins)、TIE蛋白质、内皮抑素(endostatins)等);
(j)免疫介导机制的调节剂(例如,疫苗、细胞疗法、检查点抑制剂(checkpointinhibitors)、促炎性细胞因子/抗体、佐剂等);以及
(k)蛋白酶体抑制剂如硼替佐米。
可与PAC-1有利地组合的具体化学治疗剂(活性剂或“第二活性剂”)的实例包括活性剂,如,顺铂、依托泊苷、伊立替康、康培思达(camptostar)、托泊替康、紫杉醇、多西他赛、埃博霉素、泰素帝、他莫昔芬、5-氟尿嘧啶、甲氨蝶呤(methoxtrexate)、替莫唑胺、环磷酰胺(cyclophosphamide)、SCH 66336、R115777、L778,123、BMS 214662、吉非替尼、盐酸厄洛替尼、抗EGFR抗体、伊马替尼、内含子、阿糖胞苷、环磷酰胺制剂(cytoxan)、吉西他滨、尿嘧啶氮芥、氮芥、异环磷酰胺、美法仑、苯丁酸氮芥、哌泊溴烷、三亚乙基密胺、三亚乙基硫代磷酰胺、白消安、卡莫司汀、洛莫司汀、链脲菌素、达卡巴嗪、氟尿苷、阿糖胞苷、6-巯嘌呤、6-硫鸟嘌呤、磷酸氟达拉滨、喷司他丁(pentostatine)、长春碱、长春新碱、长春地辛、博来霉素、多柔比星、放线菌素D、柔红霉素、表柔比星、伊达比星、普卡霉素、脱氧考福霉素、L-天冬酰胺酶、替尼泊苷、炔雌醇、己烯雌酚、睾酮、***、氟***、丙酸屈他雄酮、睾内酯、醋酸甲地孕酮、甲泼尼龙、***、***龙、曲安西龙、氯烯雌醚、羟孕酮、安鲁米特、雌莫司汀、甲孕酮、亮丙瑞林、氟他胺、托瑞米芬、戈舍瑞林、羟基脲、安吖啶、丙卡巴肼、米托坦、米托蒽醌、左旋咪唑、诺维本(navelbene)、阿那曲唑(anastrazole)、来曲唑、卡培他滨、reloxafine、droloxafine、六甲蜜胺、贝伐单抗、赫赛汀、百克沙(Bexxar)、泽娃灵(Zevalin)、三氧化二砷、希罗达、长春瑞滨、卟菲尔钠、西妥昔单抗、噻替派、六甲蜜胺、美法仑、曲妥珠单抗、Lerozole、氟维司群、依西美坦、氟维司群、异环磷酰胺(Ifosfomide)、利妥昔单抗、C225、Campath、卡铂、丙卡巴肼、氮芥、环磷酰胺、喜树碱、白消安、亚硝基脲(nitrosurea)、普卡霉素(plicomycin)、丝裂霉素、雷洛昔芬、***受体结合剂、诺维本、法尼酯蛋白转移酶抑制剂、transplatinum和甲氨蝶呤,或前述的任何类似物或衍生物变体。
与PAC-1或PAC-1衍生物组合时显示显著活性的化学治疗活性剂的实例包括依托泊苷、硼替佐米、十字孢碱、多柔比星、他莫昔芬、顺铂、卡铂、紫杉醇和SMAC模拟物。
与依托泊苷组合
依托泊苷是拓扑异构酶II抑制剂。依托泊苷与DNA和拓扑异构酶II酶形成三元复合物,阻止DNA链的再连接,这引起DNA合成中的错误并促进癌细胞的细胞凋亡。用PAC-1和依托泊苷的U-937细胞的联合治疗显示显著的体外活性,即使在低的微摩尔浓度下(图2)。
与硼替佐米组合
万珂(硼替佐米)以高亲和性和特异性结合26S蛋白酶体的催化位点。在正常细胞中,该蛋白酶体通过降解与泛素结合的(ubiquitinylated)蛋白质而调节蛋白表达和功能,并且还清除异常的或错误折叠的蛋白质。虽然可能涉及多种机制,但蛋白酶体抑制可阻止促细胞凋亡因子的降解,允许肿瘤细胞——依赖于促细胞凋亡途径的抑制——的程序性细胞死亡的激活。对采用PAC-1和硼替佐米的U-937淋巴瘤细胞的联合治疗,观察到协同活性(图3)。
与十字孢碱组合
十字孢碱的主要生物学活性是通过阻止ATP与激酶结合而抑制蛋白激酶,这是经由十字孢碱与该激酶上ATP结合位点的更强的亲和力而实现的。十字孢碱是典型的ATP-竞争性激酶抑制剂,因为它以高亲和性与许多激酶结合,尽管具有低选择性。缺乏特异性已经阻止了它的临床应用,但使得它成为有用的研究工具,其中十字孢碱被用于诱导细胞凋亡。十字孢碱诱导细胞凋亡的一种方式是通过激活半胱天冬酶-3。采用PAC-1和十字孢碱的U-937淋巴瘤细胞的联合治疗在低PAC-1浓度下如在7.5μM和15μM PAC-1下显示协同作用(图4)。
与多柔比星组合
多柔比星是蒽环类抗生素,它通过DNA嵌入而发挥其细胞毒素活性。多柔比星被用于治疗宽范围的癌症,包括血液肿瘤、许多类型的癌症,以及软组织肉瘤和骨肉瘤。采用PAC-1和多柔比星的143B(人OS)骨肉瘤细胞的联合治疗观察到协同活性(图5)。
与他莫昔芬组合
他莫昔芬,一种***受体的竞争性激动剂,是男性乳腺癌的最常见治疗,并被用于早期和晚期的ER+乳腺癌。他莫昔芬被批准用于在那些高风险的患者中预防乳腺癌。他莫昔芬和PAC-1的结合物具有协同作用,并在乳腺癌中提供增强的细胞杀伤效率,所述乳腺癌包括他莫昔芬阴性的或他莫昔芬抗性的乳腺癌,以及三阴性乳腺癌(图6-8)。
与顺铂组合
顺铂是用于癌症化学疗法的数种铂配位复合物中的一种。铂化合物的细胞毒性可起因于癌细胞中DNA合成的抑制。顺铂被用于治疗多种类型的癌症,包括肉瘤、癌(包括小细胞肺癌和卵巢癌)、淋巴瘤、生殖细胞肿瘤以及睾丸癌。顺铂和PAC-1的结合物可为协同的,并可在这些治疗中以及卵巢癌中提供增强的细胞杀伤效率(图9)。
与紫杉醇组合
紫杉醇,一种有丝***抑制剂(微管稳定剂),被用于治疗肺癌、卵巢癌、乳腺癌和头颈癌。紫杉醇被推荐用于治疗蒽环类(anthrocyclines)失败后的晚期乳腺癌,并被推荐不用于早期的阳性结节性乳腺癌。紫杉醇和PAC-1的结合物提供协同活性,并在这些治疗以及卵巢癌中提供增强的细胞杀伤效率(图10)。
与卡铂组合
卡铂是用于癌症化学疗法的数种铂配位复合物中的另一种。卡铂被用于治疗多种类型的癌症,主要为卵巢癌、肺癌、头颈癌。卡铂和PAC-1的结合物为协同的并可在这些治疗以及骨肉瘤中提供增强的细胞杀伤效率(图11和12)。
进一步的结合物研究
利用代表17种最近限定的乳腺癌亚型中的12种的细胞系(表1),PAC-1与标准治疗药物的致敏作用/协同作用的非致死剂量的研究正在进行中。
表1.在研究中的乳腺癌细胞系
亚型 | 细胞系 |
5 | BT20 |
5 | BT549 |
5 | Hs578T |
2 | HCC1569 |
4 | MCF7 |
4 | T47D |
6 | MDAMB361 |
7 | AU565 |
8 | HCC1954 |
9 | MDAMB231 |
10 | HCC202 |
14 | MDAMB436 |
16 | BT483 |
与多种不同的标准治疗剂组合的PAC-1也可提供可能原本不可获得的加和或协同活性。正在研究的用于组合效应的所述标准治疗剂的实例包括:
拉帕替尼,一种双重酪氨酸激酶抑制剂(EGFR和HER2),被用于HER2阳性癌症的治疗中,并且被用于三阳性乳腺癌的一线治疗中。拉帕替尼和PAC-1的结合物可在这些治疗中提供增强的细胞杀伤效率。
氟尿嘧啶(5-FU)是一种用于多种癌症治疗中的嘧啶类似物药物。它是***性抑制剂并经由不可逆的抑制胸苷酸合成酶而起效。5-FU和PAC-1的结合物在可由5-FU治疗的癌症中提供增强的细胞杀伤效率。
在不同的实施方案中,PAC-1可被替换为其类似物SPAC-1用于相似的增强、加和或协同活性。SPAC-1与常见的肿瘤学治疗剂对抗结肠、肺和肝癌细胞系的组合效应正在研究中。组合活性剂的实例、细胞系和可获得的数据输出总结于表2和表3中,其中,例如,PAC-1或SPAC-1可与任何标准剂1-4组合。
表2.用于组合效应的细胞系和活性剂
表3.在研究中的用于组合效应试验的数据,其中药物1是PAC-1或其衍生物,药物2是本文所述或所描述的活性剂。
Fa=受治疗影响的细胞的分数
可与PAC-1或其衍生物组合以提供抑制癌细胞生长或治疗特定类型癌症的增强的或协同的活性的活性剂进一步包括:
SN-38是伊立替康(喜树碱的类似物,一种拓扑异构酶I抑制剂)的活性代谢产物。SN-38比伊立替康本身的活性高200倍。伊立替康主要用于结肠癌中,具体而言,与其他化学治疗剂组合。SN-38和PAC-1的结合物可在这些治疗中提供增强的细胞杀伤效率。
奥沙利铂是用于癌症化学疗法的数种铂配位复合物中的一种。铂化合物的细胞毒性被认为起因于癌细胞中DNA合成的抑制。体内研究显示奥沙利铂经由它的(非靶向的)细胞毒性作用而具有对抗结肠癌的抗肿瘤活性。奥沙利铂和PAC-1的结合物可在这些治疗中提供增强的细胞杀伤效率。
索拉非尼是数种蛋白酪氨酸激酶(VEGFR和PDGFR)和Raf的小分子抑制剂。索拉非尼靶向MAP激酶途径(Raf/Mek/Erk途径)(MAP激酶途径),并被批准用于治疗原发性肾癌(晚期肾细胞癌)和晚期原发性肝癌(肝细胞癌)。索拉非尼和PAC-1的结合物可在这些治疗中提供增强的细胞杀伤效率。
舒尼替尼是一种口服的、小分子的、多靶标受体酪氨酸激酶(RTK)抑制剂,被FDA批准用于治疗肾细胞癌(RCC)以及伊马替尼抗性的胃肠道间质肿瘤(GIST)。舒尼替尼和PAC-1的结合物可在这些治疗中提供增强的细胞杀伤效率。
吉西他滨是用于化学疗法的核苷类似物。与氟尿嘧啶和其他嘧啶类似物一样,吉西他滨的三磷酸盐类似物在DNA复制过程中替换核酸构建模块中的一个,在该情况下是胞苷。该过程阻止肿瘤生长,因为只有一种另外的核苷可被连接于该“错误的”核苷,导致细胞凋亡。吉西他滨的另一个靶标是核糖核苷酸还原酶(RNR)。二磷酸盐类似物连接于RNR活性位点并不可逆转地使酶失活。一旦RNR被抑制,细胞不能产生DNA复制和修复所需的脱氧核糖核苷酸,从而诱导细胞凋亡。吉西他滨和PAC-1的结合物可在这些治疗中提供增强的细胞杀伤效率。
厄洛替尼是用于治疗非小细胞肺癌、胰腺癌和几种其他类型癌症的药物。它是酪氨酸激酶抑制剂,其作用于表皮生长因子受体(EGFR)。厄洛替尼和PAC-1的结合物可在这些治疗中提供增强的细胞杀伤效率。
培美曲塞是用于治疗胸膜间皮瘤以及非小细胞肺癌的化学治疗药物。培美曲塞属于被称为叶酸抗代谢药的化学治疗药物的类型。它通过抑制用于嘌呤和嘧啶合成的三种酶——胸苷酸合成酶(TS)、二氢叶酸还原酶(DHFR)和甘氨酰胺核苷酸甲酰基转移酶(GARFT)——而起效。通过抑制前体嘌呤和嘧啶核苷酸的形成,培美曲塞防止DNA和RNA的形成,DNA和RNA是正常细胞和癌细胞的生长和存活所需的。培美曲塞和PAC-1的结合物可在这些治疗中提供增强的细胞杀伤效率。
虽然利用作用于不同靶标的药物的结合物的抗癌策略具有明确的益处,然而,本文所描述的工作证实采用经由不同机制作用的化合物可观察到引人注目的协同作用。当寻求酶的激活时,该多重靶向方法可具有独特的优点。
PAC-1在哺乳动物中是安全的,并且PAC-1的衍生物在患有淋巴瘤的宠物狗的I期临床试验中是有效的(Peterson等人,Cancer Res 70,7232-7241(2010)),因此观察到的与活性剂如依托泊苷、硼替佐米、十字孢碱、多柔比星和他莫昔芬的协同作用将具有显著的临床影响。在用小分子激活酶方面的兴趣正在快速增加。本文所描述的数据表明使用PAC-1和所述互补的活性剂的靶向策略是用于显著增强预期生物学活性的一般性方法,并由于其效力将具有相当大的临床影响。
本发明的方法
本发明提供在癌细胞中选择性诱导细胞凋亡的方法,包括给予癌细胞能够修饰所述癌细胞中半胱天冬酶-3酶原分子的化合物的结合物;其中所述化合物的结合物是PAC-1和第二活性剂。还提供一种在癌细胞中选择性诱导细胞凋亡的方法,包括给予癌细胞能够修饰所述癌细胞中半胱天冬酶-3酶原分子的化合物的结合物;其中所述化合物的结合物是PAC-1和第二活性剂,例如,其中所述癌细胞位于需要治疗的患者中。
本发明提供另外的方法,其中所述化合物的结合物是PAC-1和第二活性剂,例如,作为处理癌细胞的方法,包括(a)鉴定对采用半胱天冬酶酶原激活剂化合物处理癌细胞的潜在敏感性;和(b)将所述癌细胞暴露于有效量的半胱天冬酶酶原激活剂化合物和第二活性剂的结合物。还提供一种处理癌细胞的方法,包括(a)鉴定对采用半胱天冬酶酶原激活剂化合物处理癌细胞的潜在敏感性;和(b)将所述癌细胞暴露于有效量的PAC-1和第二活性剂;其中所述PAC-1能够激活半胱天冬酶-3酶原和半胱天冬酶-7酶原中的至少一种。还提供一种在癌细胞中诱导死亡(例如,杀死癌细胞)的方法,包括给予癌细胞活性剂以及能够激活癌细胞中半胱天冬酶-3酶原分子的化合物,如PAC-1。
本发明还提供包含有效量的PAC-1和第二活性剂的结合物的药物。所述药物可用于在细胞中诱导细胞凋亡的方法中。在一些实施方案中,所述化合物的结合物不穿过血脑屏障至在患者中引起可评估的神经毒性作用的程度。本发明的方法包括使一种或多种细胞与有效量的本文所描述的化合物的结合物在体内或体外接触。因此,本发明还提供一种处理细胞的方法,包括使细胞与有效量的本文所描述的化合物的结合物接触。
如本文所描述的,本发明提供治疗具有提高的半胱天冬酶-3酶原水平的肿瘤细胞的患者的方法。所述方法可包括给予具有提高的半胱天冬酶-3酶原水平的肿瘤细胞的患者治疗有效量的本文所描述的PAC-1和第二活性剂的结合物,或其组合物。本发明还提供处理具有提高的半胱天冬酶-3酶原水平的肿瘤细胞的方法,包括将所述肿瘤细胞暴露于治疗有效量的本文所描述的PAC-1和第二活性剂的结合物,其中所述肿瘤细胞被处理、杀死或抑制生长。所述肿瘤或肿瘤细胞可以是恶性肿瘤细胞。在一些实施方案中,所述肿瘤细胞是淋巴瘤、骨肉瘤或乳腺癌细胞。
PAC-1可与第二活性剂组合,以单位剂量形式用于对患者给药。所述联合治疗可作为同时或相继的方案给药。当相继给药时,所述结合物可以两次或更多次给药进行给予。
所述联合治疗可提供“协同作用”,即活性成分一起使用时所达到的效果大于化合物单独使用所得效果之和。当PAC-1和第二活性剂如下进行时可获得协同作用:(1)在组合的制剂中,共同配制并同时给药或递送;(2)作为独立的制剂交替或平行递送;或(3)通过一些其他方案。在交替治疗中递送时,化合物被相继给药或递送后可达到协同效果,例如,在单独的片剂、丸剂或胶囊中,或通过在单独的注射器中分别注射。一般而言,在交替治疗期间,有效剂量的每一种活性成分可相继给药,即连续给药,然而在联合治疗中,有效剂量的两种或更多种活性成分一起给药。协同的抗癌效果表示抗癌效果大于结合物中各个化合物的预期的纯粹加和效果。联合治疗进一步记载于美国专利号6,833,373(McKearn等人)中,其包括可与PAC-1组合的另外的活性剂以及可用PAC-1治疗的另外类型的癌症和其他病症。
因此,PAC-1可与另一活性剂(“第二活性剂”)组合用于癌症治疗。PAC-1可经由从几分钟到几周的间隔先于或跟随第二活性剂给药。在第二活性剂和PAC-1被单独应用于细胞的实施方案中,通常应确保重要的时间段不会在每一次递送的时间之间逝去,使所述活性剂和PAC-1将仍然能够发挥对细胞的有利组合效果。例如,在这种情况下,预期细胞、组织或生物体可与两种模式基本上同时接触(即,在小于约几分钟的时间内)。在其他方面,结合物中的第二活性剂可在给予PAC-1之前和/或之后约1分钟、约5分钟、约10分钟、约20分钟、约30分钟、约45分钟、约60分钟、约2小时、约3小时、约4小时、约6小时、约8小时、约9小时、约12小时、约15小时、约18小时、约21小时、约24小时、约28小时、约31小时、约35小时、约38小时、约42小时、约45小时之内,或在约48小时或更长的时间内给药。在某些其他实施方案中,第二活性剂可在给予PAC-1之前和/或之后约1天、约2天、约3天、约4天、约5天、约6天、约8天、约9天、约12天、约15天、约16天、约18天、约20天或约21天之内给药。然而,在一些情况下,可能希望显著延长治疗的时间段,其中各次给药之间间隔几周(例如,约1、约2、约3、约4、约6或约8周或更多周)。
本发明的化学治疗组合物对患者的给药将通常遵循用于化学治疗剂给药的一般方案,如果有毒性时需加以考虑。预期必要时可重复治疗周期。还预计多种标准疗法或附助癌症疗法,以及手术介入,可与所描述的结合物联合应用。这些疗法包括但不限于化学治疗、免疫疗法、基因疗法和手术。
药物制剂
可将本文所述的化合物用于制备治疗性药物组合物,例如,通过将所述化合物与药学上可接受的稀释剂、赋形剂或载体结合。可将所述化合物以盐或溶剂化物形式加到载体中。例如,在化合物具有足够的碱性或酸性以形成稳定的无毒性酸盐或碱盐的情况下,作为盐的化合物的给予可能是合适的。药学上可接受的盐的实例是与形成生理上可接受的阴离子的酸所形成的有机酸加成盐,例如,甲苯磺酸盐、甲磺酸盐、乙酸盐、柠檬酸盐、丙二酸盐、酒石酸盐、琥珀酸盐、苯甲酸盐、抗坏血酸盐、α-酮戊二酸盐和β-甘油磷酸盐。也可形成适合的无机盐,包括氢氯化物、卤化物、硫酸盐、硝酸盐、碳酸氢盐和碳酸盐。
可使用本领域熟知的标准方法获得药学上可接受的盐,例如,通过使足够碱性的化合物(例如胺)与合适的酸反应以提供生理上可接受的离子化合物。也可通过类似的方法制备羧酸的碱金属(例如,钠、钾或锂)或碱土金属(例如钙)盐。
可将本文所述的化合物制成药物组合物并将其以多种形式给予哺乳动物宿主(例如人类患者)。所述形式尤其适于所选择的给药途径,所述途径例如口服或胃肠外给药,通过静脉内、肌肉内、局部或皮下途径。
可将本文所述的化合物与药学上可接受的载体(如惰性稀释剂或可吸收的食用载体)结合来全身给药。可通过使用环糊精(例如2-羟丙基-β-环糊精)来提高活性物质的溶解度。对于口服给药,可将化合物包封在硬壳或者软壳明胶胶囊中,压缩成片剂、或直接掺入到患者饮食的食物中。化合物也可与一种或多种赋形剂结合,并以可吸收的片剂、***片、锭剂、胶囊、酏剂、悬浮液、糖浆剂、薄片剂等形式使用。这样的组合物和制剂通常包含至少0.1%的活性化合物。所述组合物和制剂的百分比可以改变并且可方便地为给定的单位剂型的重量的约1%到约60%,或约2%到约25%。活性化合物在这种治疗有效的组合物中的量使得可获得有效的剂量水平。
片剂、锭剂、丸剂、胶囊剂等也可包含下面的一种或多种:粘合剂如黄蓍胶、***胶、玉米淀粉或明胶;赋形剂如磷酸氢钙;崩解剂如玉米淀粉、马铃薯淀粉、海藻酸等;润滑剂如硬脂酸镁。可以添加甜味剂如蔗糖、果糖、乳糖或阿司帕坦;或调味剂如薄荷、冬青油、或樱桃调味剂。当所述单位剂型是胶囊时,除了上述类型的材料,其可能还包含液态载体如植物油或聚乙二醇。多种其他材料可能作为包衣层存在或者另外修饰固体单位剂型的物理形式。例如,可用明胶、蜡、紫胶或糖等包覆片剂、丸剂或胶囊剂。糖浆剂或酏剂可包含活性化合物、作为甜味剂的蔗糖或果糖、作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯、染料和调味香料如樱桃或甜橙香料。用于制备任何单位剂型的任何材料应为药学上可接受的并且所用的量基本无毒性。此外,可将活性化合物掺入到缓释制剂和设备中。
可通过输注或注射将活性化合物静脉内或腹腔内给药。可在水中制备活性化合物或其盐的溶液,任意地与无毒的表面活性剂混合。可在甘油、液体聚乙二醇、三乙酸甘油酯或其混合物,或在药学上可接受的油中制备分散剂。在正常的存储和使用的条件下,制剂可包含防腐剂以防止微生物的生长。
适用于注射或输注的药物剂型可包括含有活性组分的无菌水溶液、分散剂或无菌粉末,所述活性成分适用于无菌的可注射的或可输注的溶液或分散剂的即用制剂,任选地被包封在脂质体中。最终的剂型在生产和储藏的条件下应该是无菌的、流体的和稳定的。所述液体载体或媒介物可能是溶剂或液体分散介质,其包含例如,水、乙醇、多元醇(例如,甘油、丙二醇、液体聚乙二醇等)、植物油、无毒性甘油酯、和它们的合适混合物。例如,可通过形成脂质体、通过在分散剂的情况下维持所需的颗粒大小、或通过使用表面活性剂来维持适当的流动性。可通过多种抗菌剂和杀真菌剂(例如,对羟基苯甲酸酯类、氯丁醇、苯酚、山梨酸、乙基汞硫代水杨酸钠等)来预防微生物作用。在很多情况中,优选包括等渗剂,例如糖、缓冲液或氯化钠。可通过药剂延迟吸收(例如单硬脂酸铝和/或明胶)来引起可注射的组合物的延长的吸收。
可通过将合适溶剂中的活性化合物以所需量与以上列举的多种其他成分整合(根据需要,任选随后进行过滤灭菌)来制备无菌的可注射溶液。在用于制备无菌的可注射溶液的无菌粉末的情况下,制备方法可包括真空干燥和冷冻干燥技术,其产生之前无菌过滤的溶液中存在的活性成分和任何其他所需成分的粉末。
通过比较本文所述化合物在动物模型中的体外活性和体内活性来确定它们的有用剂量。将小鼠和其他动物中的有效剂量外推至人类的方法是本领域已知的;例如,参见美国专利4,938,949(Borch等人)。用于治疗所需的化合物、或其活性盐或衍生物的量不仅会随着所选择的具体化合物或盐而改变,还随着给药途径、正被治疗的病症的性质、以及患者的年龄和状况而改变,并且最后听凭主治医师或临床医生的决定。
化合物的结合物可方便地以单位剂型给予,例如,每单位剂型包含100-5,000mg/m2、300-4,000mg/m2、370-3,700mg/m2、50-750mg/m2、或750-4,000mg/m2的活性成分。每个化合物也可单独或组合地以约1mg/kg-约250mg/kg、约10mg/kg-约100mg/kg、约10mg/kg-约50mg/kg、约50mg/kg-约100mg/kg、约10mg/kg-约50mg/kg、或约10mg/kg、约25mg/kg、约50mg/kg、约75mg/kg、约100mg/kg、或约150mg/kg,或从上述值中任何一个到上述值中任何其他一个的范围给药。还可将所述化合物给予受试者以提供约1μmol/L-约25μmol/L、或约10μmol/L、或约15μmol/L的单独或组合的药物的稳定-状态血浆浓度。
在一些实施方案中,本发明提供了约10nM到约100μM的有效浓度的化合物。在另一个实施方案中,有效浓度从约200nM到约50μM、约500nM到约40μM、约750nM到约25μM、约1μM到约20μM,或约1μM到约10μM。在另一个实施方案中,有效浓度被认为是一个值,如在直接的半胱天冬酶酶原激活试验中、细胞凋亡诱导试验中、或动物临床治疗评估中的50%的活性浓度。在一个实施方案中,所述值小于约200μM。在另一个实施方案中,所述值小于约10μM,但大于约10nM。所需剂量可方便地以单一剂量存在,或作为以合适的间隔给药的分开剂量(例如,每天两个、三个、四个或更多个子剂量)存在。所述子剂量本身可被进一步分成,例如,很多离散松散间隔的给药。
本文所述的化合物可以是有效的抗肿瘤剂并且与任何单一药剂的给药相比具有更高的效力和/或降低的毒性。本发明提供在哺乳动物中治疗癌症的治疗方法,所述方法包括将有效量的本文所述的化合物或组合物给予具有癌症的哺乳动物。哺乳动物包括灵长类动物、人类、啮齿动物、犬、猫、牛、羊、马、猪、山羊、牛等。癌症是指任何多种类型的恶性肿瘤,例如,本文所述的其中的结肠癌、乳腺癌、黑素瘤和白血病,并且通常癌症由不需要的细胞增殖(例如不受调控的生长、分化的缺乏、局部组织侵入、和转移)来表征。
可通过使用本领域熟知的试验来确定本发明化合物治疗癌症的能力。例如,治疗方案的设计、毒性评估、数据分析、肿瘤细胞杀死数量、以及使用可移植肿瘤筛选的生物学意义都是已知的。另外,可使用上述以及本文引用的文献和专利文件中的实验来确定化合物治疗癌症的能力。
本发明还提供化合物的前药形式。会在体内被转化以提供PAC-1或本文所述的另一活性剂的任何化合物都是前药。形成前药的多种方法是本领域熟知的。前药和制备它们的方法的实例存在于,尤其是,Design of Prodrugs,由H.Bundgaard编辑,(Elsevier,1985),Methods in Enzymology,Vol.42,at pp.309-396,由K.Widder等人编辑(AcademicPress,1985);A Textbook of Drug Design and Development,由Krosgaard-Larsen andH.Bundgaard编辑,Chapter 5,″Design and Application of Prodrugs,″byH.Bundgaard,at pp.113-191,1991);H.Bundgaard,Advanced Drug Delivery Reviews,Vol.8,p.1-38(1992);H.Bundgaard等人,Journal of Pharmaceutical Sciences,Vol.77,p.285(1988);and Nogrady(1985)Medicinal Chemistry A Biochemical Approach,Oxford University Press,New York,pages 388-392)。
另外,在一些实施方案中,可将PAC-1替换为PAC-1衍生物或其他抑制剂,如记载于美国专利7,632,972(Hergenrother等人)、美国专利公布文本2012/0040995(Hergenrother等人)和2007/0049602(Hergenrother等人),以及美国申请序列号12/597,287(Hergenrother等人)中的化合物。可与本文公开内容结合使用的用于癌症治疗的有用的化合物、方法和技术记载于上述文件、以及美国专利6,303,329(Heinrikson等人)、6,403,765(Alnemri)、6,878,743(Choong等人)和7,041,784(Wang等人)、和美国专利公布文本2004/0180828(Shi)中。
如Putt等人,Nature Chemical Biology 2006,2(10),543-550;Peterson等人,J.Mol.Biol.2009,388,144-158;和Peterson等人,Cancer Res.2010,70(18),7232-7241所记载的,可进行用于执行测试和评价癌细胞系的方法。
以下实施例旨在说明以上发明并不应被理解为缩小它的范围。本领域技术人员会很容易地意识到实施例暗示了可实施本发明的许多其他方法。应理解,可以做出许多改变和修改,但是仍在本发明的范围内。
实施例
实施例1.药物剂型
以下制剂举例说明了代表性的可用于本文所述的结合物化合物、或其药学上可接受的盐或溶剂化物(下文称为“化合物X”)的治疗或预防性给药的药物剂型:
可用药学领域中公知的常规方法制备这些制剂。可以理解,可根据公知的制药技术将上述药物组合物进行改变以容纳不同的量和类型的活性成分“化合物X”。气溶胶制剂(vi)可与标准的、计量剂量气溶胶分配器联用。另外,具体的成分和比例用于说明性目的。根据所需的目的剂型的特性,可将成分换成适当的等价物并且可改变比例。
当参考所公开的实施方案和实施例如上描述具体的实施方案时,这样的实施方案只是说明性的,并不限制本发明的范围。可由本领域普通技术人员做出改变和修饰,而不背离如下面的权利要求中所定义的具有更宽泛方面的本发明。
所有的出版物、专利和专利文件均通过引用的方式纳入本文,尽管通过引用单独纳入。与本公开内容不一致的限定不应理解为来自本公开内容。参考各种具体的和优选的实施方案和技术对本发明进行了描述。但是,应理解可在本发明的精神和范围内做出很多改变和修改。
Claims (26)
1.一种组合物,包括
(a)化合物PAC-1:
(b)第二活性剂,其中所述第二活性剂是硼替佐米、十字孢碱、多柔比星、他莫昔芬、顺铂、卡铂或紫杉醇,以及
(c)药学上可接受的载体。
2.权利要求1的组合物,其中所述载体包括水和任选地缓冲剂、环糊精或其结合物。
3.权利要求2的组合物,其中所述环糊精是2-羟丙基-β-环糊精。
4.权利要求1的组合物,其中PAC-1的浓度为约2μM至约50μM,其中“约”指具体指明的数值的±10%的变化。
5.权利要求1的组合物,其中所述第二活性剂的浓度为约25nM至约1mM,其中“约”指具体指明的数值的±10%的变化。
6.权利要求1-5中任一项的组合物,其中所述第二活性剂是硼替佐米,并且硼替佐米的浓度为约50nM至约20μM,其中“约”指具体指明的数值的±10%的变化。
7.权利要求1-5中任一项的组合物,其中所述第二活性剂是十字孢碱,并且十字孢碱的浓度为约25nM至约200nM,其中“约”指具体指明的数值的±10%的变化。
8.权利要求1-5中任一项的组合物,其中所述第二活性剂是多柔比星,并且多柔比星的浓度为约50nM至约5μM,其中“约”指具体指明的数值的±10%的变化。
9.权利要求1-5中任一项的组合物,其中所述第二活性剂是他莫昔芬,并且他莫昔芬的浓度为约5μM至约50μM,其中“约”指具体指明的数值的±10%的变化。
10.权利要求1-5中任一项的组合物,其中所述第二活性剂是顺铂,并且顺铂的浓度为约5μM至约150μM,其中“约”指具体指明的数值的±10%的变化。
11.权利要求1-5中任一项的组合物,其中所述第二活性剂是卡铂,并且卡铂的浓度为约5μM至约150μM,其中“约”指具体指明的数值的±10%的变化。
12.权利要求1-5中任一项的组合物,其中所述第二活性剂是紫杉醇,并且紫杉醇的浓度为约0.5nM至约5nM,其中“约”指具体指明的数值的±10%的变化。
13.权利要求1-12中任一项的组合物用于制备抑制癌细胞生长或增殖的药物的用途。
14.权利要求13的用途,其中所述癌细胞是淋巴瘤细胞、骨肉瘤细胞、乳腺癌细胞或卵巢癌细胞。
15.权利要求1-12中任一项的组合物用于制备诱导癌细胞凋亡的药物的用途。
16.一种在癌细胞中诱导细胞凋亡的非治疗目的的方法,包括使癌细胞与有效量的化合物PAC-1和有效量的第二活性剂在体外接触,
其中所述第二活性剂是硼替佐米、十字孢碱、多柔比星、他莫昔芬、顺铂、卡铂或紫杉醇;从而在癌细胞中诱导细胞凋亡。
17.权利要求16的方法,其中所述癌细胞与PAC-1和第二活性剂同时接触。
18.权利要求16的方法,其中在所述癌细胞与所述第二活性剂接触之前使所述癌细胞与PAC-1接触。
19.权利要求16的方法,其中在所述癌细胞与所述第二活性剂接触之后使所述癌细胞与PAC-1接触。
20.权利要求1-12中任一项的组合物用于制备治疗癌症的药物的用途。
21.权利要求20的用途,其中所述癌症是淋巴瘤、骨肉瘤、乳腺癌或卵巢癌。
22.权利要求1-5中任一项的组合物,其中PAC-1的浓度为约7.5μM至约30μM,其中“约”指具体指明的数值的±10%的变化。
23.权利要求1-5中任一项的组合物,其中
所述第二活性剂是硼替佐米,并且硼替佐米的浓度为约100nM至约5μM;或
所述第二活性剂是十字孢碱,并且十字孢碱的浓度为约50nM至约100nM;或
所述第二活性剂是多柔比星,并且多柔比星的浓度为约100nM至约1000nM;或
所述第二活性剂是他莫昔芬,并且他莫昔芬的浓度为约2.5μM至约15μM;或
所述第二活性剂是顺铂,并且顺铂的浓度为约30μM至约100μM;或
所述第二活性剂是卡铂,并且卡铂的浓度为约25μM至约100μM;或
所述第二活性剂是紫杉醇,并且紫杉醇的浓度为约1nM至约3nM,其中“约”指具体指明的数值的±10%的变化。
24.权利要求23的组合物,其中所述第二活性剂是他莫昔芬,并且他莫昔芬的浓度为约5μM至约15μM,其中“约”指具体指明的数值的±10%的变化。
25.权利要求24的组合物,其中所述第二活性剂是他莫昔芬,并且他莫昔芬的浓度为约10μM至约15μM,其中“约”指具体指明的数值的±10%的变化。
26.权利要求23的组合物,其中所述第二活性剂是卡铂,并且卡铂的浓度为约50μM至约100μM,其中“约”指具体指明的数值的±10%的变化。
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