CN114302722A - 雌激素受体拮抗剂方案 - Google Patents
雌激素受体拮抗剂方案 Download PDFInfo
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- CN114302722A CN114302722A CN202080059997.1A CN202080059997A CN114302722A CN 114302722 A CN114302722 A CN 114302722A CN 202080059997 A CN202080059997 A CN 202080059997A CN 114302722 A CN114302722 A CN 114302722A
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Abstract
本文提供了施用雌激素受体拮抗剂以用于治疗癌症的方法。所述拮抗剂(如六氢吡啶并[3,4‑b]吲哚、AZD9496、RAD‑1901、ARN‑810、因多昔芬或氟维司群)可以是雌激素受体的激活功能1和激活功能2两者的抑制剂。还提供了上述抑制剂与作为CDK4/6抑制剂(如帕博西尼、瑞博西尼、阿贝西尼、莱罗西尼和曲拉西尼)的第二剂的组合。
Description
相关申请的交叉引用
本申请要求2019年7月7日提交的美国临时申请号62/871,191和2019年7月8日提交的美国临时申请号62/871,592的优先权,所述申请各自的全部内容特此以引用的方式并入。
背景技术
雌激素受体(ER)在包括乳腺癌在内的各种癌症中发挥着重要作用。已经开发了多种治疗来靶向雌激素受体和/或其活性。
发明内容
仍然需要能够完全抑制雌激素受体的抗雌激素剂,包括由编码雌激素受体-α(ERα)、雌激素受体1(ESR1)的基因的野生型和突变型型式(例如,含有激活突变的那些)编码的那些。选择性雌激素受体调节剂(SERM)或降解剂(SERD)是可用于这种疗法的特别有用或有前景的工具。雌激素受体是包含两种不同的转录激活功能(AF1和AF2)的三联蛋白。完全抗雌激素活性需要AF1和AF2两者的失活。编码雌激素受体1的基因中的激活突变即使在没有雌激素的情况下也能激活AF1和AF2两者。
以前的疗法,如他莫昔芬、AZD9496和ARN-810未能使两种激活功能失效(即,不能使AF1和AF2两者失效)。因此,仍然需要使AF1和AF2两者失效以完全抑制雌激素受体的疗法,并且此外,仍然需要尽管激活突变仍能抑制雌激素受体的疗法。本公开尤其记载了某些化合物(单独或与其它剂组合)可用作患有癌症的患者或受试者的治疗,并且其中所述患者或受试者携带雌激素受体1(ESR1)的突变。例如,在一些实施方案中,可用于治疗患有癌症的患者或受试者的化合物是化合物1,并且其中所述患者或受试者携带雌激素受体1(ESR1)的突变:
在一些实施方案中,本公开提供了一种治疗患有与雌激素受体(ER)相关的癌症的患者或受试者的方法,所述方法包括施用雌激素受体拮抗剂和CDK4/6抑制剂。
在一些实施方案中,本公开提供了一种治疗患有与雌激素受体(ER)相关的癌症的患者或受试者的方法,所述方法包括施用雌激素受体拮抗剂和PIK3CA抑制剂。
在一些实施方案中,本公开提供了一种治疗患有与雌激素受体(ER)相关的癌症的患者或受试者的方法,所述方法包括施用雌激素受体拮抗剂和mTOR抑制剂。
在一些实施方案中,本公开提供了一种治疗患有癌症的患者或受试者的方法,其中所述癌症已转移至脑、骨、肺或肝,所述方法包括向所述患者或受试者施用化合物1:
在一些实施方案中,本公开提供了一种用于评估用于抑制雌激素受体激活功能1(AF1)和/或激活功能2(AF2)的化合物或组合物的测定系统。
在一些实施方案中,本公开提供了一种用于治疗患有癌症的患者的方法,所述方法包括口服施用化合物1。
附图说明
图1A是对于未添加雌激素的某些雌激素受体拮抗剂化合物,测量随Log[M]变化的雌激素反应百分比的散点图。
图1B是对于添加了雌激素的某些雌激素受体拮抗剂化合物,测量随Log[M]变化的雌激素反应百分比的散点图。
图2是测量多种雌激素受体拮抗剂跨多种细胞系的雌激素受体蛋白的降解的图表。
图3A-3C是示出化合物1与各种CDK4/6抑制剂组合的雌激素反应的百分比降低的散点图。
图4A-4B是示出当用化合物1与PIK3CA抑制剂的组合治疗时,针对MCF-7细胞的雌激素增殖的百分比降低的散点图。
图5A-5F是示出化合物1对具有最常见ESR1突变的AF1抑制的剂量反应的细胞系的散点图。
图6是示出对于不同剂量的化合物1,肿瘤体积的变化的散点图。
图7A-7D是测量小鼠(7A)、大鼠(图7B)、狗(图7C)和猴(图7D)随时间推移的药物暴露(ng/ml)的散点图。
图8A-8D是示出不同细胞系中雌激素浓度降低的散点图。
图9是示出突变型ER增加Ishikawa子宫内膜癌细胞中的配体非依赖性碱性磷酸酶活性(AP)的条形图。
图10是示出ER的激活结构域1(AF1)为AP活性所需的条形图。
图11是Patel和Bihani Pharm&Therap 186:1,2018的图1A的再现,示出哺乳动物表达两种主要的ER同种型,称为ERα和ERβ,它们中的每一者均是核激素受体家族的成员。A)构成雌激素受体的A-F结构域,其包括激活功能1(AF1)结构域、DNA结合结构域(DBD)、铰链区和配体结合机构域(LBD)/激活功能2(AF2结构域)。B)内分泌疗法(芳香酶抑制剂、SERM和SERD)对雌激素受体途径的影响。芳香酶抑制剂通过抑制雌二醇的合成来阻止ER信号传导,SERM通过与ER结合并产生无活性复合物来阻止ER信号传导,并且SERD通过导致ER降解来阻止ER信号传导。
图12是Hewitt和Korach Endocrine Rev.39:664-674(2018年6月12日)的图3的再现,其示出E2反应的基本机制的变化。
具体实施方式
仍然需要克服与先前方法相关的问题的雌激素受体(ER)阳性癌症类型的疗法。本公开尤其提供了治疗患有与雌激素受体和雌激素受体的突变相关的癌症的患者或受试者的方法,所述方法包括施用雌激素受体拮抗剂。在一些实施方案中,所述雌激素受体拮抗剂是化合物1:
或其药学上可接受的盐。
定义
施用:如本文所用,术语“施用”通常是指将组合物施用至受试者或系统,例如以实现作为所述组合物或包含在所述组合物中或以其它方式由所述组合物递送的剂的递送。
剂:如本文所用,术语“剂”是指实体(例如,脂质、金属、核酸、多肽、多糖、小分子等,或其复合物、组合、混合物或系统[例如,细胞、组织、生物体]),或现象(例如,热、电流或电场、磁力或磁场等)。
拮抗剂:如本文所用,术语“拮抗剂”可指其存在、水平、程度、类型或形式与靶标的水平或活性降低相关的剂或条件。拮抗剂可包括任何化学类别的剂,包括例如小分子、多肽、核酸、碳水化合物、脂质、金属和/或显示相关抑制活性的任何其它实体。在一些实施方案中,拮抗剂可以是“直接拮抗剂”,因为它直接与其靶标结合;在一些实施方案中,拮抗剂可以是“间接拮抗剂”,因为它通过与其靶标直接结合以外的方式施加其影响;例如,通过与靶标的调控剂相互作用,从而改变靶标的水平或活性)。在一些实施方案中,“拮抗剂”可被称为“抑制剂”。
相关:两个事件或实体彼此“相关”,如果一者的存在、水平和/或形式与另一者的存在、水平、程度、类型和/或形式关联,则在本文中使用所述术语。例如,如果特定实体(例如多肽、遗传签名、代谢物、微生物等)的存在、水平和/或形式与疾病、病症或疾患的发生率和/或易感性关联(例如,在相关群体中),则认为所述特定实体与所述特定疾病、病症或疾患相关。在一些实施方案中,如果两个或更多个实体直接或间接地相互作用,使它们彼此在物理上接近和/或保持在物理上接近,则它们在物理上彼此“相关”。在一些实施方案中,物理上彼此相关的两个或更多个实体彼此共价连接;在一些实施方案中,物理上彼此相关的两个或更多个实体彼此不共价连接,而是非共价缔合,例如通过氢键、范德华相互作用、疏水相互作用、磁性及其组合。
生物样品:如本文所用,术语“生物样品”通常是指如本文所述获自或源自目标生物来源(例如,组织或生物体或细胞培养物)的样品。在一些实施方案中,目标来源包括生物体,诸如动物或人。在一些实施方案中,生物样品是或包括生物组织或流体。在一些实施方案中,生物样品可以是或包括骨髓;血液;血细胞;腹水;组织或细针活检样品;含有细胞的体液;自由浮动核酸;痰;唾液;尿;脑脊液、腹腔液;胸膜液;粪便;淋巴液;妇科流体;皮肤拭子;阴道拭子;口腔拭子;鼻拭子;冲洗物或灌洗物,例如导管灌洗物或支气管肺泡灌洗物;抽吸物;刮片;骨髓标本;组织活检标本;外科标本;粪便、其它体液、分泌物和/或排泄物;和/或来自其中的细胞等。在一些实施方案中,生物样品是或包括从个体获得的细胞。在一些实施方案中,获得的细胞是或包括来自获得样品的个体的细胞。在一些实施方案中,样品是通过任何适当的方式直接从目标来源获得的“初级样品”。例如,在一些实施方案中,初级生物样品通过选自由以下组成生物组的方法获得:活检(例如,细针抽吸或组织活检)、外科手术、体液(例如,血液、淋巴液、粪便等)的收集等。在一些实施方案中,从上下文可以清楚地看出,术语“样品”是指通过对初级样品进行加工(例如,通过除去一种或多种组分和/或通过添加一种或多种剂)而获得的制剂。例如,使用半透膜过滤。这种“经加工的样品”可包括例如从样品中提取的或通过使初级样品经受诸如mRNA的扩增或逆转录、某些组分的分离和/或纯化等的技术获得的核酸或蛋白质。
组合疗法:如本文所用,术语“组合疗法”是指其中受试者同时暴露于两种或更多种治疗方案(例如,两种或更多种治疗剂)的那些情况。在一些实施方案中,可同时施用两种或更多种方案;在一些实施方案中,可依次施用此类方案(例如,在施用第二方案的任何剂量之前施用第一方案的所有“剂量”);在一些实施方案中,以重叠给药方案施用此类剂。在一些实施方案中,组合疗法的“施用”可涉及向接受组合中的其它剂或模式的受试者施用一种或多种剂或模式。为清楚起见,组合疗法不要求单独的剂在单一组合物中一起施用(或甚至必须同时施用),但在一些实施方案中,两种或更多种剂或其活性部分可在组合组合物中或甚至在组合化合物中一起施用(例如,作为单一化学复合物或共价实体的一部分)。
剂型或单位剂型:本领域技术人员将理解,术语“剂型”可用于指用于向受试者施用的活性剂(例如,治疗剂或诊断剂)的物理离散单元。通常,每个这样的单元含有预定量的活性剂。在一些实施方案中,这种量是适合根据给药方案施用的单位剂量的量(或其整个部分),所述单位剂量的量已被确定为与当施用至相关群体时的所需或有益结果(即,与治疗剂量方案)相关。本领域普通技术人员了解,向特定受试者施用的治疗性组合物或剂的总量由一名或多名主治医师确定并且可能涉及多种剂型的施用。
给药方案或治疗方案:本领域技术人员将理解,术语“给药方案”和“治疗方案”可用于指通常相隔时间段来单独施用于受试者的一组单位剂量(通常多于一个)。在一些实施方案中,给定的治疗剂具有推荐的给药方案,其可涉及一个或多个剂量。在一些实施方案中,给药方案包括多个剂量,每个剂量在时间上与其它剂量分开。在一些实施方案中,单独剂量彼此间隔相同长度的时间段;在一些实施方案中,给药方案包括多个剂量,并且单独剂量间隔至少两个不同的时间段。在一些实施方案中,给药方案内的所有剂量具有相同的单位剂量量。在一些实施方案中,给药方案内的不同剂量具有不同的量。在一些实施方案中,给药方案包括第一剂量量的第一剂量,随后是与第一剂量量不同的第二剂量量的一个或多个另外剂量。在一些实施方案中,给药方案包括第一剂量量的第一剂量,随后是与第一剂量量相同的第二剂量量的一个或多个另外剂量。在一些实施方案中,当跨相关群体施用时,给药方案与所需或有益的结果相关(即,是治疗性给药方案)。
赋形剂:如本文所用,术语“赋形剂”是指可包含在药物组合物中,例如以提供或促成所需的稠度或稳定作用的非治疗剂。合适的药物赋形剂包括例如,淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂乳粉、甘油、丙烯、乙二醇、水、乙醇等。
口服:如本文所用的短语“口服施用(oral administration)”和“口服施用(administered orally)”具有它们的在本领域中理解的含义,是指通过口腔来施用化合物或组合物。
胃肠外:如本文所用的短语“胃肠外施用(parenteral administration)”和“胃肠外施用(administered parenterally)”具有它们的在本领域中理解的含义,是指除经肠和局部施用以外的施用模式,通常通过注射来进行,并且包括但不限于静脉内、肌肉内、动脉内、鞘内、囊内、眶内、心内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜、脊椎内和胸骨内注射和输注。
患者或受试者:如本文所用,术语“患者”或“受试者”是指例如出于实验、诊断、预防、美容和/或治疗的目的而施用或可施用所提供的组合物的任何生物体。典型的患者或受试者包括动物(例如,哺乳动物,如小鼠、大鼠、兔、非人灵长类动物和/或人)。在一些实施方案中,患者是人。在一些实施方案中,患者或受试者患有或易患一种或多种病症或疾患。在一些实施方案中,患者或受试者展现病症或疾患的一种或多种症状。在一些实施方案中,患者或受试者已被诊断患有一种或多种病症或疾患。在一些实施方案中,患者或受试者正在接受或已经接受某种疗法以诊断和/或治疗疾病、病症或疾患。
药物组合物:如本文所用,术语“药物组合物”是指与一种或多种药学上可接受的载体一起配制的活性剂。在一些实施方案中,活性剂以适合于在相关受试者的治疗方案中(例如,以已证明在施用时显示达到预定治疗效果的统计学显著概率的量)或在不同的、可比较的受试者中(例如,在与目标受试者或系统不同的可比较的受试者或系统中在目标特定疾病、病症或疾患的一种或多种适应症存在下,或在先前暴露于疾患或剂等)施用的单位剂量量存在。在一些实施方案中,比较术语是指统计上相关的差异(例如,其流行率和/或量级足以达到统计上的相关性)。在给定的上下文中,本领域技术人员将意识到或将能够容易地确定对于实现这种统计显著性所需或足够的差异的程度和/或流行率。
药学上可接受的载体:如本文所用,术语“药学上可接受的载体”是指将主题化合物从身体的一个器官或部分携带或运输至身体的另一器官或部分时涉及的药学上可接受的材料、组合物或媒介物,如液体或固体填充剂、稀释剂、赋形剂或溶剂囊封材料。各载体在可与制剂的其它成分相容并且对患者无害的意义上必须是“可接受的”。可充当药学上可接受的载体的材料的一些实例包括:糖,如乳糖、葡萄糖和蔗糖;淀粉,如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;粉状黄蓍胶;麦芽糖;明胶;滑石;赋形剂,如可可脂和栓剂蜡;油,如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇,如丙二醇;多元醇,如甘油、山梨糖醇、甘露糖醇和聚乙二醇;酯,如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,如氢氧化镁和氢氧化铝;海藻酸;无热原水;等渗盐水;林格氏溶液(Ringer’s solution);乙醇;pH缓冲溶液;聚酯、聚碳酸酯和/或聚酸酐;以及其它用于药物制剂中的无毒可相容材料。
药学上可接受的盐:如本文所用的术语“药学上可接受的盐”是指适用于药物背景下的此类化合物的盐,即在合理医学判断的范围内适用于与人和低等动物的组织接触而无过度毒性、刺激、过敏反应等,并且与合理益处/风险比相称的盐。药学上可接受的盐是本领域熟知的。例如,S.M.Berge等人在J.Pharmaceutical Sciences,66:1-19(1977)中详细描述了药学上可接受的盐。在一些实施方案中,药学上可接受的盐包括但不限于:无毒酸加成盐,其为氨基与无机酸(如盐酸、氢溴酸、磷酸、硫酸和高氯酸)或与有机酸(如乙酸、顺丁烯二酸、酒石酸、柠檬酸、丁二酸或丙二酸)或通过使用本领域中使用的其它方法(如离子交换)形成的盐。在一些实施方案中,药学上可接受的盐包括但不限于己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙烷磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐(pamoate)、果胶酸盐(pectinate)、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。代表性碱金属或碱土金属盐包括钠、锂、钾、钙、镁等。在一些实施方案中,适当时,药学上可接受的盐包括使用平衡离子如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、具有1至6个碳原子的烷基、磺酸根和芳基磺酸根形成的无毒铵、季铵和胺阳离子。
治疗剂:如本文所用,短语“治疗剂”一般是指当向生物体施用时引发所需的药理学作用的任何剂。在一些实施方案中,如果剂在整个适当的群体中表现出统计学显著的效应,则所述剂被认为是治疗剂。在一些实施方案中,适当的群体可以是模型生物体的群体。在一些实施方案中,可通过各种标准来定义适当的群体,所述标准诸如某个年龄组、性别、遗传背景、预先存在的临床条件等。在一些实施方案中,治疗剂是可用于减轻、改善、缓和、抑制、预防疾病、病症和/或疾患、延迟其发作、减轻其严重性、和/或降低其一种或多种症状或特征的发生率的物质。在一些实施方案中,“治疗剂”是已经或需要由政府机构批准才可销售以向人施用的剂。在一些实施方案中,“治疗剂”是需要医学处方才能施用于人的剂。
治疗:如本文所用,术语“治疗(treat、treatment或treating)”是指用于部分或完全减轻、改善、缓和、抑制、预防疾病、病症和/或疾患,延迟其发作,降低其严重性和/或降低其一种或多种症状或特征的发生的任何方法。可向未表现出疾病、病症和/或疾患的迹象的受试者施用治疗。在一些实施方案中,可向仅展现疾病、病症和/或疾患的早期迹象的受试者施用治疗,例如以达成降低发展与所述疾病、病症和/或疾患相关的病理的风险的目的。
治疗有效量:如本文所用,术语“治疗有效量”是指物质(例如治疗剂、组合物和/或制剂)在作为治疗方案的一部分施用时引发所需生物反应的量。在一些实施方案中,物质的治疗有效量是当向罹患或易感疾病、病症和/或疾患的受试者施用时足以治疗、诊断、预防所述疾病、病症和/或疾患和/或延迟其发作的量。如本领域普通技术人员将了解,物质的有效量可取决于如所需生物终点、待递送的物质、靶标细胞或组织等的因素而变化。例如,制剂中的化合物的用以治疗疾病、病症和/或疾患的有效量是减轻、改善、缓和、抑制、预防所述疾病、病症和/或疾患、延迟其发作、降低其严重性和/或降低其一种或多种症状或特征的发生的量。在一些实施方案中,治疗有效量以单个剂量施用;在一些实施方案中,递送治疗有效量需要多个单位剂量。
雌激素受体
雌激素受体(“ER”)参与例如与女性生殖系统的发育、骨量的维持、心血管和/或中枢神经系统组分的保护等有关的多种生物过程(参见例如,Pearce和JordanCrit.Rev.Onc/Hem 50:3,2004;Heldring Phys.Rev.87:905,2007)。
哺乳动物表达ER的两种主要同种型,称为ERα和ERβ,它们中的每一者均是核激素受体家族的成员并且具有如图11中再现的Patel和Bihani Pharm&Therap 186:1,2018的图1A中描绘的结构组织。如图11中所示:A)构成雌激素受体的A-F结构域,其包括激活功能1(AF1)结构域、DNA结合结构域(DBD)、铰链区和配体结合机构域(LBD)/激活功能2(AF2结构域)。B)内分泌疗法(芳香酶抑制剂、SERM和SERD)对雌激素受体途径的影响。芳香酶抑制剂通过抑制雌二醇的合成来阻止ER信号传导,SERM通过与ER结合并产生无活性复合物来阻止ER信号传导,并且SERD通过导致ER降解来阻止ER信号传导。
可以看出,在ER结构中定义了标记为A-F的六个ER“结构域”。位于ER蛋白的氨基末端的结构域A/B是最大的结构域,并且包含两个所谓的“转录激活功能”元件之一,AF1;AF2位于E结构域中,其还包含据信参与ER二聚化和核定位的配体结合结构域和元件(参见例如,Hewitt和Korach Endocrine Rev 39:664,2018)。据信,配体与配体结合结构域的结合触发E结构域内α螺旋的结构重组,并且这种重组可能有助于AF2的活性(例如,与某些介质组分相互作用)。
ER的C结构域包括其DNA结合结构域,它介导与所谓的“雌激素反应元件”(ERE)相互作用,所述雌激素反应元件与转录受ER调控的基因可操作地缔合。ERα和ERβ调控不同ERE相关基因的表达,并且显示出不同的细胞和组织分布模式。ER的DNA结合似乎由C结构域内的两个锌指结构介导,尽管一个或多个另外的元件可能有所贡献(参见例如,Hewitt和Korach Endocrine Rev 39:664,2018)。ER的C结构域也可参与或以其它方式促成ER二聚化。
ER的D结构域也称为“铰链区”并且包括可参与ER二聚化和/或核定位的氨基酸元件。
ER的F结构域可在ER蛋白稳定性中起作用。与其它核受体家族成员相比,此结构域似乎是雌激素受体的特征,并且可促成对某些疗法(例如他莫昔芬)的反应性(参见例如,Arao等人,J.Bio.Chem293:22,8495)。
在天然配体(例如17β-雌二醇)存在下,ER经历构象变化、同二聚化并定位于细胞核,在细胞核中它与ERE结合并调控其靶基因的转录(参见例如,Pawlak等人;Kumar和Chambor;Hall和McDonnell);此系列事件被描述为ER基因调控的“基因组”机制。还描述了其它机制,如“栓系”、“非基因组”和“配体独立性”,如图12中再现的Hewitt和Korach的图3中所描绘。
如图12所示并且由Hewitt和Korach报告,E2反应的基本机制的变化。已经描述了四种不同的E2反应机制。(1)基因组机制涉及ER与ERE DNA基序之间的相互作用。(2)栓系机制涉及ER与其它转录调控因子(如结合FOS/JUN二聚体的AP1 DNA基序)之间的间接相互作用。因此,在此实例中,通过FOS/JUN与其AP1 DNA基序的结合将ER“栓系”至DNA。(3)非基因组信号是所谓的,因为它启动来自细胞外E2的信号,从而产生细胞质中的快速信号级联,并且因此所述反应不涉及与基因组特征的相互作用。这些反应由膜相关ER或GPER(一种G蛋白偶联受体)介导。(4)不依赖配体的信号传导涉及细胞膜GF受体(GFR)的细胞外生长因子(GF)激活的转导,从而起始信号传导级联,如MAPK。尽管缺乏E2配体,但ER接收信号,从而激活其对靶基因的转录调节。
ER一直牵涉于多种癌症中。在许多表达雌激素受体的肿瘤(即ER+肿瘤)中,活性ERα信号传导已被证明驱动细胞增殖(尽管据报告ERβ信号传导能够实现肿瘤抑制效应;参见例如,Nilsson和Gustafson Clin.Pharmacol.Ther.89:44,2011)。通常,只有1%的细胞呈ER染色阳性的肿瘤(例如乳腺肿瘤)被分类为“ER+”。
靶向ER的治疗是许多ER+肿瘤患者的标准治疗(参见例如,Cardoso等人AnnalsOnc.https://doi.org/10.1093/announc/mdmx036,2017;Rugo等人J.Clin.Oncol.34:3069,2016;Senkus等人Annal Onc.26:v8,2015;Sareddy和Vadlamudi Clin.J Nat.Med,13:801,2015)。例如,对于早期乳腺癌患者,推荐的疗法通常包括肿瘤切除,然后是ER靶向疗法(例如,如下文所论述)。对于晚期乳腺癌(包括转移性乳腺癌),ER靶向疗法是主流。
雌激素受体靶向疗法
鉴于ER信号传导在许多癌症以及某些心血管、炎症和神经变性疾病中的重要性,已投入大量精力来开发靶向ER的治疗剂和模式。用于描述ER靶向剂的术语具有一定的流动性/灵活性,但已经开发和/或研究了具有不同机制的各种剂。
一些ER靶向剂被设计和/或记录用于降低雌激素(即,17β雌二醇)的产生水平。
一些ER靶向剂被设计和/或记录为直接与ER结合;在一些情况下,此类剂与雌激素竞争结合至ER和/或干扰雌激素结合将自然产生的变构变化。通常,术语“抗雌激素”用于指与ER结合的剂,并且有时专门用于表示与雌激素竞争ER结合的剂。
术语“选择性雌激素受体调节剂”(“SERM”)已被用来指被设计和/或记录为改变ER活性的一些方面的化合物。一些著作将“SERM”称为代表一种特定类型的抗雌激素;然而,其它著作更普遍地使用术语“SERM”来指代化合物,所述化合物具体地影响ER(特别是ERα)表达和/或活性的一些特征。
术语“选择性雌激素受体降解剂”(“SERD”)已用于指被设计和/或记录为触发或增强ER降解的化合物。在许多情况下,如果化合物的存在与ER水平降低相关,则所述化合物可被称为SERD。一些著作将化合物分类为SERM或SERD;其它著作将SERD称为特定类型或种类的作为SERM的化合物。
不管特定剂的作用机制如何,迄今为止的临床经验表明,不完全效应(例如,在单个患者内和/或跨患者群体)和/或耐药性的发展仍然是问题。
此外,据报告某些ER突变的存在或发展影响各种ER靶向疗法的有效性(参见例如,Jeselsohn等人Nature Rev.Clin.Onc.12,573,2015;Gelsomino等人Breast CancerRes.Treat 157:253,2016;Toy等人2013)。一些特别有问题的突变是“激活”ER表达和/或功能的一个或多个方面的那些突变;据报告,一些激活突变可使ER配体独立(即组成型活性)。例如,ER配体结合结构域中的特定突变(包括D538G和Y537S)已被证明组成性地激活ER;其它突变(包括除去配体结合结构域的缺失和/或融合)可具有类似的效应(参见例如,Li等人Cell Repts 4:1116,2013;Veeraraghavan等人Breast Cancer Research and Treatment158,219–232,2016;Veeraraghavan等人Nature Comms5:4577,2014)。一些报告表明,多达50%的患有转移性乳腺癌的女性可在循环肿瘤DNA中检测到激活ER突变。
雌激素受体拮抗剂
如上所述,为了寻求靶向ER的有效疗法,已经并将继续进行大量投资(例如,在Patel&Bihani Pharmacol.&Therap.186:1,2018中进行了综述)。
临床开发中最先进的化合物包括:
a.他莫昔芬一直是一种重要的乳腺癌治疗剂,被誉为“挽救了全世界50万妇女的生命”(参见“在NCI的支持下将研究性乳腺癌药物Endoxifen从实验室带到床边,可在https://www.cancer.gov/news-events/cancer-currents-blog/2017/endoxifen- breast-cancer-NCI-support获得(最后访问时间为2019年7月7日),但已知对低CYP2D6活性的女性效果较差,并且也容易发展耐药性。
b.因多昔芬(Endoxifen)是他莫昔芬的活性代谢物,最初开发用于解决他莫昔芬在低CYP2D6活性的女性中失败的问题,其降低所述女性将他莫昔芬转化为因多昔芬的能力。(参见Cancer Currents Blog,National Cancer Institute,2017年8月31日)。
c.ARN-810(布利司群(Brilanestrant);GDC-810),其被描述为“可在他莫昔芬敏感性和耐药性ER+BC异种移植物模型中诱导肿瘤消退的新型的、有效的、非类固醇的、口服生物可利用的选择性ER拮抗剂/ER降解剂”(参见Dickler等人Cancer Res.75(15增补版):摘要nr CT231,2015),并且已进入II期临床试验,用于治疗其它激素剂治疗失败但进一步发展可能随后已下降的ER+乳腺癌患者(参见例如,Biospace2017年4月27日)。
d.AZD9496,其被描述为“雌激素受体α(ERα)的口服非类固醇小分子抑制剂和ERα的强效且选择性拮抗剂和降解剂”(参见Hamilton等人Clin Cancer Res 1:3519,2018);据报告,AZD9496“拮抗和降解ER,在内分泌敏感性和内分泌耐药性模型两者中均具有抗肿瘤活性”,并被描述为“在拮抗ER和规避内分泌耐药性方面与氟维司群相当”(参见Nardone等人Br.J.Cancer 120:331,2019)。
e.RAD-1901(依拉司群(Elacestrant))被描述为“已在大量预先治疗的ER+晚期乳腺癌患者中显示出单剂活性的新型非类固醇口服SERD(参见de Vries等人,Cancer Res.摘要P1-10-04,2018;还参见Bardia等人J.Clin.Onc.35:15_suppl,1014,2017)。临床前研究还报告,“依拉司群显著抑制了携带ESR1突变的异种移植物模型的生长,包括携带Y537S或D538G突变的那些模型以及对氟维司群和他莫昔芬不敏感的模型”(参见Patel等人CancerRes 79:摘要nr P6-20-08,2019)。
f.氟维司群(FaslodexTM)是第一个获得FDA批准的SERD,并且已被批准用于治疗某些ER+癌症,包括与帕博西尼或阿贝西尼组合使用。氟维司群是“结合、阻断和降解雌激素受体(ER)、从而完全抑制通过ER进行的雌激素信号传导的选择性雌激素受体降解剂”(参见Nathan和Schmid Oncol Ther 5:17,2017)。氟维司群已取得显著临床成功,并且通常被认为是比较ER靶向疗法的“黄金标准”。然而,氟维司群是通过注射而不是口服施用的,并且实际上需要每月一次通过肌肉内注射施500mg(在初始给药后)。此外,尽管某些回顾性分析提供了希望,即氟维司群可能在治疗具有ER突变体的患者中具有一些效用,但尚未获得确凿的活性证据(参见例如,Fribbens等人J Clin Oncol.34:2961,2916;Spoerke等人NatCommun 7:11579,2016):
本公开认识到,氟维司群的成功源于其作为完全雌激素受体拮抗剂(“CERAN”)发挥作用的能力,所述拮抗剂(1)抑制AF1和AF2两者,因此它能够抑制在组成型活性ER突变体中仍然存在的AF1活性;(2)促进ER降解;并且(3)缺乏在某些其它剂情况下观察到的部分ER激动剂活性(参见例如,图1A,其尤其记录ARN-810、AZD-9496和因多昔芬中的每一者在不存在添加的雌激素情况下增加ER活性,即使在雌激素存在时降低ER活性)。例如,与限制雌激素产生的疗法(例如阿那曲唑)或部分拮抗剂(例如他莫昔芬)相比,氟维司群表现出优异的活性并且是激素受体阳性的局部晚期或转移性乳腺癌患者的优选治疗选择。参见Robertson等人,The Lancet,388(10063):2997-3005(2016年12月17日)。不希望受任何特定理论束缚,提出氟维司群抑制AF1和AF2的能力可归因于其将共阻遏因子募集至ER复合物。
无论如何,本公开进一步认识到许多其它化合物,包括例如ARN-810、AZD9496、他莫昔芬等不如氟维司群有效,至少部分是因为它们仅部分拮抗ER,并且特别是因为它们抑制AF2的激活但不抑制AF1的激活。
本公开提供了重要且出人意料的见解,即先前描述的化合物,(1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-1-(4-((1-丙基氮杂环丁烷-3-基)氧基)苯基)-2,3,4,4a,9,9a-六氢-1H-吡啶并[3,4-b]吲哚(“化合物1”;参见PCT申请公布号WO 2017/059139,其全部内容以引用的方式并入)
与氟维司群的CERAN属性相匹配,并且此外还提供其它有价值的性质,包括例如它(i)具有口服生物可利用性且具有长半衰期;并且(ii)显示出良好的血脑屏障渗透性。本公开尤其证明化合物1在某些情况下是独特有用的,包括用于(a)治疗与ER突变相关的癌症,包括配体非依赖性/组成性突变;(b)治疗具有CNS(例如脑)转移或肿瘤的癌症;(c)与某些其它剂组合使用,包括已证明或提出可与氟维司群一起使用的某些剂。
例如,本公开尤其报告以下发现,化合物1表现出完全雌激素受体拮抗作用,而且这种拮抗作用在各种测定中与氟维司群相当。除其它方面外,如实施例4中所报告,本公开证明化合物1的特征在于抑制AF1和AF2的能力,并且因此被恰当地描述为“完全雌激素受体拮抗剂”。
本公开教导化合物1对于治疗与一种或多种ER突变体,特别是包括配体非依赖性ER突变体的存在相关的疾病、病症或疾患(例如,癌症)可能特别有用或有效。因此,在一些实施方案中,本公开提供了治疗方法,其中向表达(例如,在相关细胞或组织中)一种或多种ER,特别是一种或多种配体非依赖性ER的受试者施用化合物1;在一些实施方案中,已证明此类受试者在施用前表达此类突变型ER。
本领域技术人员将知道允许检测来自受试者的样品中的突变型ER的多种技术。在一些实施方案中,检测突变型ER蛋白;在一些实施方案中,检测编码突变型蛋白(例如突变型ESR1基因)的核酸。
尽管雌激素受体(例如,ESR1)的激活突变,化合物1抑制AF1和AF2的能力仍允许化合物1起到CERAN的作用。
因此,在一些实施方案中,本公开提供了治疗患有癌症的受试者(或受试者群体)的方法,其中所述受试者携带ESR1突变(和/或表达突变型ER蛋白),所述方法包括向所述受试者施用化合物1:
或其药学上可接受的盐。
ER拮抗剂的评估
本公开尤其教导有用的ER拮抗剂是具有如本文所述的CERAN活性的那些。
本公开的一个方面是以下见解,即用于评估或表征ER拮抗剂(和/或潜在拮抗剂)的常规策略是不够的,至少因为它们通常不区分SERD和CERAN。特别地,大多数此类常规策略并未评估剂具体影响AF1的能力。
本公开尤其教导特别有用的ER拮抗剂是能够抑制配体非依赖性ER活性的那些;在一些实施方案中,包括在组成型ER变体,例如AF2缺失或截短和/或LBD突变体(例如D538G和Y537S)情况下观察到的活性。
此外,本公开教导特别有用的ER拮抗剂的特征在于以下中的每一者:
a.制AF1(例如,抑制至少一种且优选所有已知的组成型ER变体)
b.制AF2(例如,抑制配体依赖性ER活性)
c.进ER降解
此外,在一些实施方案中,特别有用的ER拮抗剂的特征还在于以下中的一者或多者:
a.服生物利用度和长半衰期。
b.脑屏障渗透。
在特定实施方案中,可相对于ARN-810、AZD9496、因多昔芬、氟维司群、RAD1901、他莫昔芬和/或化合物1中的一者或多者的活性来评估ER拮抗剂的活性;在一些此类实施方案中,比较是同时进行的,或者可替代地,在一些实施方案中,它可与历史记录或未来结果进行比较。
组合疗法
本公开进一步提供了以下见解,即化合物1作为AF1和AF2两者的抑制剂的独特能力使其在某些组合疗法中的使用特别有吸引力。如图3A-3B(对于CDK4/6抑制剂)和图4A-4B(对于PIK3CA抑制剂)所示,化合物1(一种雌激素受体拮抗剂且实际上是一种完全雌激素受体拮抗剂)与第二剂组合可基本上消除细胞增殖。本公开包括涵盖以下认识,即某些剂的组合可有益地用于通过使AF1和AF2失活来完全拮抗雌激素受体。因此,在一些实施方案中,本公开提供了一种治疗患有癌症的受试者的方法,所述方法包括施用作为激活功能2的抑制剂的化合物和作为激活功能1的抑制剂的第二剂。在一些实施方案中,其中所述化合物是选自AZD9496、RAD-1901、ARN-810、因多昔芬、氟维司群和化合物1的雌激素受体拮抗剂。在一些实施方案中,所述化合物选自氟维司群和化合物1。
在一些实施方案中,本公开提供了一种治疗患有癌症的患者或受试者的方法,所述方法包括施用化合物1和选自CDK2、CDK4、CDK6或CDK7抑制剂的第二剂。在一些实施方案中,第二剂是CDK2抑制剂。在一些实施方案中,第二剂是CDK4抑制剂。在一些实施方案中,第二剂是CDK6抑制剂。在一些实施方案中,第二剂是CDK7抑制剂。在一些实施方案中,第二剂是CDK4/6抑制剂(即,抑制CDK4和CDK6中的一者或两者)。在一些实施方案中,第二剂是CDK2/4/6抑制剂(即,抑制CDK2、CDK4和CDK6中的一者或多者)。
在一些实施方案中,第二剂是选自帕博西尼(palbocociclib)、瑞博西尼(ribociclib)、阿贝西尼(abemaciclib)、莱罗西尼(lerociclib)、曲拉西尼(trilaciclib)和SHR6390的CDK4/6抑制剂。在一些实施方案中,CDK 4/6抑制剂是帕博西尼。在一些实施方案中,CDK4/6抑制剂是瑞博西尼。在一些实施方案中,CDK4/6抑制剂是阿贝西尼。在一些实施方案中,CDK4/6抑制剂是莱罗西尼。在一些实施方案中,CDK4/6抑制剂是曲拉西尼。在一些实施方案中,CDK 4/6抑制剂是SHR6390。
在一些实施方案中,本公开提供了一种治疗患有癌症的患者或受试者的方法,所述方法包括施用化合物1和第二剂,其中所述第二剂是PIK3CA抑制剂。在一些实施方案中,PIK3CA抑制剂选自阿培利司(alpelisib)、他塞利司(taselisib)和LY3023414。在一些实施方案中,PIK3CA抑制剂是阿培利司。在一些实施方案中,PIK3CA抑制剂是他塞利司。在一些实施方案中,PIK3CA抑制剂是LY3023414。
在一些实施方案中,本公开提供了一种治疗患有癌症的患者或受试者的方法,所述方法包括施用化合物1和第二剂,其中所述第二剂是mTOR抑制剂。在一些实施方案中,mTOR抑制剂选自西罗莫司、替西罗莫司(temsirolimus)、依维莫司和LY3023414。在一些实施方案中,mTOR抑制剂是西罗莫司。在一些实施方案中,mTOR抑制剂是替西罗莫司。在一些实施方案中,mTOR抑制剂是依维莫司。在一些实施方案中,mTOR抑制剂是LY3023414。
给药
本公开涵盖以下认识,即某些病症或疾患(例如癌症)可使用少于具有类似活性的其它化合物的量的活性化合物来有效治疗。例如,如图6所示,发现化合物1比其它CERAN(例如氟维司群)更有效地减小肿瘤体积。此外,化合物1适合口服施用,这相对于其它必须胃肠外施用的CERAN(例如氟维司群)是有益的。
因此,本公开提供了一种治疗患有癌症的患者或受试者的方法,所述方法包括施用包含化合物1的组合物。在一些实施方案中,所述组合物包含化合物1和药学上可接受的赋形剂、载体或稀释剂。所述组合物可口服、胃肠外、通过吸入或鼻喷雾、局部(例如,通过粉末、软膏或滴剂)、直肠、经颊、阴道内、腹膜内、脑池内或通过植入储库施用,这取决于所治疗疾患的严重程度。优选地,所述组合物口服、腹膜内或静脉内施用。在某些实施方案中,所提供的化合物以每天约0.01mg/kg至约50mg/kg受试者体重的剂量水平口服或胃肠外施用,每天一次或多次,以获得所需的治疗作用。
本文所述的药学上可接受的药物组合物可以任何口服上可接受的剂型口服施用,所述剂型包括但不限于胶囊、片剂、水性悬浮液或溶液。在此类固体剂型中,活性化合物可与至少一种惰性稀释剂如蔗糖、乳糖或淀粉混合。按照一般的惯例,此类剂型还可包含除惰性稀释剂以外的其它物质,例如,润滑剂和其它压片助剂,如硬脂酸镁和微晶纤维素。当需要用于口服使用的水性悬浮液时,将活性成分与乳化剂和悬浮剂组合。如果需要,还可添加某些甜味剂、调味剂或着色剂。
用于口服施用的固体剂型包括胶囊、片剂、丸剂、粉末和颗粒剂。在此类固体剂型中,活性化合物与至少一种药学上可接受的惰性赋形剂或载体(如柠檬酸钠或磷酸二钙)和/或以下物质混合:a)填充剂或增量剂,如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸;b)粘合剂,例如像羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶;c)湿润剂,如甘油;d)崩解剂,如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;e)溶解阻滞剂,如石蜡;f)吸收促进剂,如季铵化合物;g)润湿剂,例如像鲸蜡醇和甘油单硬脂酸酯;h)吸收剂,如高岭土和膨润土;和/或i)润滑剂,如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠,以及它们的混合物。在胶囊、片剂和丸剂的情况下,剂型还可包含缓冲剂。活性化合物还可以是具有如上所述的一种或多种赋形剂的微囊化形式。
在使用诸如乳糖(lactose或milk sugar)以及高分子量聚乙二醇等的赋形剂的软填充和硬填充明胶胶囊中也可使用类似类型的固体组合物作为填充剂。可制备具有诸如肠溶包衣(即缓冲剂)和药物配制领域中熟知的其它包衣的包衣和外壳的片剂、糖衣丸、胶囊、丸剂以及颗粒剂的固体剂型。它们可任选地含有乳浊剂,并且还可具有使其在肠道的某一部分中任选地以延迟方式仅仅或优先释放活性成分的组成。可使用的包埋组合物的实例包括聚合物质和蜡。
用于口服施用的液体剂型包括但不限于药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。除活性化合物外,液体剂型还可含有本领域中常用的惰性稀释剂,诸如水或其它溶剂;增溶剂和乳化剂,诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(尤其棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯以及它们的混合物。除惰性稀释剂外,口服组合物还可包含佐剂,诸如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂和芳香剂。
可替代地,本文所述的药学上可接受的组合物可以栓剂的形式施用以用于直肠或阴道施用。这些可通过将本申请的化合物与合适的非刺激性赋形剂或载体混合来制备,所述赋形剂或载体在室温下为固体,但在体温(例如直肠或阴道)温度下为液体,并且因此将在直肠或阴道腔中融化以释放活性化合物。此类材料包括可可脂、栓剂蜡(例如蜂蜡)和聚乙二醇。
在一些实施方案中,所述组合物口服施用。在一些实施方案中,所述组合物以30mg/kg患者或受试者体重或更少的量施用。在一些实施方案中,所述组合物以10mg/kg患者或受试者体重或更少的量施用。在一些实施方案中,所述组合物以10、9、8、7、6、5、4、3、2或1mg/kg患者或受试者体重的量施用。在一些实施方案中,所述组合物以3mg/kg患者或受试者体重或更少的量施用。在一些实施方案中,所述组合物以1mg/kg患者或受试者体重或更少的量施用。在一些实施方案中,所述组合物以0.9、0.8、0.7、0.6、0.5、0.4、0.3、0.2或0.1mg/kg患者或受试者体重的量施用。在一些实施方案中,所述组合物以0.1mg/kg患者体重的量施用。
在一些实施方案中,化合物1以单位剂型施用。在一些实施方案中,化合物1以胶囊的形式施用。在一些实施方案中,化合物以片剂的形式施用。在一些实施方案中,化合物1以悬浮液的形式施用。在一些实施方案中,化合物1以溶液的形式施用。
在一些实施方案中,化合物1以每日剂量(QD)施用。在一些实施方案中,化合物1以每日两次剂量(BID)施用。在一些实施方案中,化合物1每隔一天(QOD)施用。在一些实施方案中,化合物1以每周剂量(QW)施用。在一些实施方案中,化合物1以每月剂量(Q4W)施用。
如图7A-7D所示,随时间推移的药物暴露(ng/ml)是高的,并且甚至对于小鼠(图7A)、大鼠(图7B)、狗(图7C)和猴(图7D)受试者也是如此。
病症或疾患
本公开还涵盖以下认识,即化合物1可有利地用于治疗转移性癌症,例如已经扩散至脑、骨、肺、肝或中枢神经系统的癌症。如下表所示,当以单次口服300mg/kg剂量施用时,化合物1能够穿透血脑屏障。其它雌激素受体拮抗剂(例如氟维司群)不能以类似的量穿透血脑屏障。
基质 | 组 | 剂量 | 剂量单位 | 浓度(ng/ml) |
血浆 | 化合物1 10mpk | 10 | mg/kg | 1919 |
血浆 | 化合物1 30mpk | 30 | mg/kg | 5558 |
脑 | 化合物1 10mpk | 10 | mg/kg | 2147 |
脑 | 化合物1 30mpk | 30 | mg/kg | 9708 |
脑 | 氟维司群5mg qw | 5 | mg | 501 |
因此,本公开提供了一种治疗患有已转移至脑、骨、肺、肝或中枢神经系统的癌症的患者或受试者的方法,所述方法包括施用化合物1:
在一些实施方案中,癌症包括一种或多种CNS肿瘤(例如,转移);在一些实施方案中,癌症已转移至脑、骨、肺或肝。在一些实施方案中,癌症已转移至中枢神经系统。
实施例
本文提供的实施例记录并支持本公开的某些方面,但不意图限制任何权利要求的范围。除非以过去时明确表示,否则包括在实施例中并不意图暗示所描述的工作已经完成或甚至进行。提供以下非限制性实施例以进一步说明本公开所提供的某些教义。根据本申请,本领域技术人员将了解,在不脱离本教义的精神和范围的情况下,可对本发明实施例中说明的具体实施方案进行各种改变。
在以下实施例中可使用以下缩写:aq.(水性);ACN(乙腈);CSA(樟脑磺酸);d(天(day)或天(days));DCM(二氯甲烷);DEA(二乙胺);DHP(二氢吡喃);DMF(N,N-二甲基甲酰胺);DIPEA(N,N-二异丙基乙胺);DMAP(4-二甲基氨基吡啶);DMSO(二甲基亚砜);EA(乙酸乙酯);ee(对映体过量);equiv.(当量);乙醇(EtOH);h(小时(hour)或小时(hours));Hex(己烷);HPLC(高效液相色谱);IPA(异丙醇);KHMDS(双(三甲基甲硅烷基)氨基钾);LAH(氢化铝锂);LCMS(液相色谱-质谱);LDA(二异丙基氨基锂);LiHMDS(双(三甲基甲硅烷基)氨基锂);MeOH(甲醇);min(分钟(minute)或分钟(minutes));NMR(核磁共振);Pd/C(钯碳);PPh3O(三苯基氧化膦);Pt/C(铂碳);rb(圆底);Rf(保留因子);rt或RT(室温);SM(起始材料);TEA(三乙胺);THF(四氢呋喃);THP(四氢吡喃);TLC(薄层色谱);TsOH(对甲苯磺酸或甲苯磺酸);和UV(紫外线)。
实施例1:
化合物1的合成
化合物1的完整合成在PCT申请公布号WO 2017/059139中提供(所述申请以引用的方式并入本文)并在下文重复。
4-((1-丙基氮杂环丁烷-3-基)氧基)苯甲醛的制备
步骤1:1-丙酰基氮杂环丁-3-酮的制备
将化合物3-氮杂环丁酮盐酸盐(10000g,93.0mmol,1.0当量)、无水1,2-二氯乙烷(200mL)和二异丙基乙胺(38.9mL,223mmol,2.4当量)添加至圆底烧瓶(500mL)中以提供淡黄色悬浮液。将所述悬浮液超声处理1小时,然后冷却至-10℃(干冰/MeOH)持续10分钟。将丙酰氯(9.8mL,112mmol,1.2当量)逐滴添加至冷却的悬浮液中以提供橙色溶液。从浴中移除反应物且在室温下搅拌16小时。除去溶剂以提供半固体。将半固体悬浮于EA(300mL)中并过滤悬浮液。将固体用EA(2x100mL)冲洗。TLC分析(10%MeOH/DCM,KMnO7染色/加热)表明存在三个斑点:Rf:0.2、0.5、0.7。TLC(50%EA/Hex,KMnO7染色/加热)表明存在两个斑点:Rf:1、0.3。将滤液浓缩,吸附到硅胶(25g)上并通过硅胶(100g盒)用DCM(5分钟)、然后0%-10%MeOH经15分钟进行色谱分析。产物在DCM中较早从柱中流出,并继续用至多10%MeOH从柱中洗脱。在两种溶剂系统中进行TLC以确定早期级分中是否存在任何丙酰氯。将含有产物的级分合并并浓缩以提供呈黄色液体的标题化合物(11.610g,98.2%)。
1H NMR(300MHz,CDCl3)δ:4.80(d,J=5.6Hz,4H),2.29(q,J=7.5Hz,2H),2.01(s,3H),1.18(t,J=7.5Hz,3H)。
步骤2.1-丙基氮杂环丁-3-醇的制备
将氢化铝锂(10.397g,273.9mmol,3.0当量)悬浮于THF(200mL)中并在冰浴中冷却。将1-丙酰基氮杂环丁-3-酮(11.610g,91.3mmol,1.0当量)于THF(100mL)中的溶液经由压力均衡加料漏斗在30分钟内逐滴添加至反应混合物中。移除加料漏斗。然后将烧瓶配备冷凝器,并将反应物在75℃的油浴中在回流下加热16小时。将反应物在冰浴中冷却20分钟,并在20分钟内以小份添加十水硫酸钠(芒硝,25g)。完成添加后,将混合物在室温下搅拌2小时。将混合物通过床(2cm)过滤并用EA(2x250mL)冲洗固体。将澄清溶液浓缩成淡黄色液体(9.580g,91.1%)。NMR表明存在THF和EA。此物质无需进一步纯化即可用于制备以下实施例的化合物。
1H NMR(300MHz,CDCl3)δ:4.39(pent,J=6Hz,1H),3.62–3.56(m,2H),2.90–2.85(m,2H),2.41(t,J=7.5Hz,2H),1.34(hextet,J=7.2Hz,2H),0.87(t,J=7.8Hz,3H)。
(R)-1-(1H-吲哚-3-基)-N-((R)-1-苯乙基)丙-2-胺的制备:
在N2下在25℃下将吲哚-3-丙酮(25.0g,144mmol,1.0当量)添加至(R)-(+)-1-苯乙胺(23.0mL,181mmol,1.3当量)于二氯甲烷(600mL)中的溶液,并将混合物搅拌1小时。将反应物冷却至0℃-5℃,并在30分钟内通过粉末加料漏斗将三乙酰氧基硼氢化钠(100g,472mmol,3.3当量)添加至冰冷却的溶液中。将橙色溶液在0℃下搅拌1小时,然后温至室温。将反应物在室温搅拌19小时。此时,ESI+表明不存在吲哚起始材料。在10℃和剧烈搅拌下,在15分钟内以5mL部分添加饱和NaHCO3溶液(100mL)。将溶液搅拌15分钟并在15分钟内添加饱和Na2CO3溶液(200mL)。以3g部分添加固体K2CO3(9g),此时水层为pH 12且气泡已停止形成。过滤且分离各层。将红色有机层用饱和NaHCO3水溶液(2x100mL)洗涤。合并水层并用DCM(2x100mL)萃取。将合并的有机层经Na2SO4干燥,过滤并浓缩,以得到粗产物(49g)。TLC(90:10DCM:MeOH)显示四个斑点(Rf=0.63、0.50、0.16、0.26),其中两个是分离的非对映异构体主要产物(Rf=0.16和0.26)。将粗产物吸附到硅胶上并通过快速色谱法(330g盒,0%-100%EA:Hex)纯化。合并含有R,R非对映异构体的级分,并使用相同的快速色谱条件进行第二次纯化,得到24g的产物(约82%ee)。之前成功的分离是通过40:1的硅胶:粗产物比例实现的,因此将混合物分成3部分并在3x330g硅胶盒上分离(0%-40%EA/Hex持续20分钟,等度40%EA/Hex 40分钟)。含有所需产物的所有级分是>99%非对映异构纯。将纯级分浓缩并合并以产生呈橙色半固体的(R)-1-(1H-吲哚-3-基)-N-((R)-1-苯乙基)-丙-2-胺(11.91g,29.6%)。
1H NMR(CDCl3,300MHz)R,R非对映异构体:δ0.96(d,J=6.6Hz,3H),1.30(d,J=6.6Hz,3H),2.68(q,J=7.2Hz,1H),2.97(m,2H)4.00(q,J=6.3Hz,1H),7.43-6.97(m,10H),7.96(br s,1H)。R,S非对映异构体:δ1.11(d,J=5.7Hz,3H),1.30(d,J=5.4Hz,3H)2.80(m,3H),3.92(q,J=6.9Hz,1H),6.93-7.40(m,10H),8.13(br s,1H);由于缺乏纯度,芳香族区域难以与R,R非对映异构体区分开。
LCMS:ES+[M+H]+279.0。
(2R)-1-(1H-吲哚-3-基)丙-2-胺的制备
将化合物(R)-1-(1H-吲哚-3-基)-N-((R)-1-苯乙基)丙-2-胺(11.91g,42.8mmol,1.0当量)溶解于甲醇(250mL)中并添加至2L Parr瓶中,并将溶液用N2鼓泡10分钟。添加用水润湿的20%碳载Pd(OH)2(10.71g,76.3mmol,1.8当量),并用50psi氢气对瓶进行加压并在Parr装置中振荡22小时,LCMS分析指示反应完成。通过过滤悬浮液并浓缩以除去MeOH。将粗产物溶解于DCM中并用饱和Na2CO3溶液(50mL)洗涤,并用DCM(2x50mL)萃取水层。将有机层合并,干燥并浓缩,得到无需进一步纯化的呈浅棕色固体的(2R)-1-(1H-吲哚-3-基)丙-2-胺(6.68g,89.6%)。
1H NMR(CDCl3,300MHz)δ1.17(d,J=6.6Hz,3H),2.66(dd,J=8.4,14.7Hz,1H),2.88(dd,J=5.4,14.1Hz,1H),3.27(sextet,J=1.5Hz,1H),7.05-7.22(m,3H),7.37(d,J=7.5Hz,1H),7.62(d,J=8.7Hz,1H),8.00(br s,1H)。
LCMS:ES+[M+H]+174.9。
2-氟-2-甲基丙醇的制备
在15分钟内将2-氟-2-甲基丙酸甲酯(5.01g,40.5mmol,1.0当量)逐滴添加至在冰浴中冷却的氢化铝锂(2.50g,65.9mmol,1.6当量)于无水乙醚(100mL)中的搅拌溶液。2小时后,依次逐滴添加2.0mL水、2.0mL 15%w/v NaOH和5.0mL水。15分钟后,将白色悬浮液用DCM稀释,通过重力过滤,并将固体用DCM洗涤。将滤液浓缩(200毫巴,25℃),得到呈无色油状的2-氟-2-甲基丙醇(2.09g,56.1%)。
1H NMR(300MHz,CDCl3)δ1.34(d,J=21.3Hz,6H),1.95(br t,1H),3.56(dd,J=6.6,20.7Hz,2H)。
三氟甲磺酸2-氟-2-甲基丙基酯的制备
在30分钟内将三氟甲磺酸酐(5.0mL,29.7mmol,1.3当量)逐滴添加至2-氟-2-甲基丙醇(2.090g,22.7mmol,1.0当量)和2,6二甲基吡啶(3.40mL,29.4mmol,1.3当量)于DCM(25mL)中的0℃溶液。2小时后,红色溶液变成浅棕色。TLC(20:80EA:Hex,KMnO4染色)表明不存在起始材料。将反应混合物用1M HCl溶液(2x20mL)和饱和NaHCO3溶液(2x20mL)洗涤。将水层各自用DCM(20mL)反萃取。将合并的有机层用Na2SO4干燥,过滤并在减压(150毫巴,25℃)下浓缩,得到呈红色油状的三氟甲磺酸2-氟-2-甲基丙基酯(4.39g,86.3%)。
1H NMR(300MHz,CDCl3)δ1.46(d,J=20.4Hz,6H),4.41(d,J=18.6Hz,2H).19F NMR(282MHz,CDCl3)δ-147.1,-74.5。
(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2-氟-2-甲基丙-1-胺的制备:
将化合物三氟甲磺酸2-氟-2-甲基丙基酯(9.587g,42.8mmol,1.1当量)(DCM中的溶液,按wt%计16%DCM,11.4384g)添加至(2R)-1-(1H-吲哚-3-基)丙-2-胺(6.680g,38.3mmol,1.0当量)、无水1,4-二噁烷(60.000ml,701.4mmol,18.3当量)和新鲜蒸馏的二异丙基乙胺(8.500ml,48.8mmol,1.3当量)的溶液。将深棕色溶液在90℃下加热3小时。3小时后,LCMS指示仍存在少量吲哚胺起始材料。TLC(10%MeOH/DCM)指示三氟甲磺酸酯(Rf=0.54)已用完。未使用的三氟甲磺酸酯SM(286-30)的NMR指示三氟甲磺酸酯未过夜分解,因此添加另外0.1当量(0.9883g,13%DCM wt%,0.8563g三氟甲磺酸酯SM)并将反应物在90℃下加热2小时。LCMS指示反应已经完成并且TLC(10%MeOH/DCM)显示一个斑点(Rf=0.24)(TLC使用50%EA/Hex,1个条纹斑点Rf<=0.12,另一个斑点在Rf=0)。添加EtOAc(50mL)并将溶液用NaHCO3(2x50mL)洗涤,并将合并的水层用EtOAc(50mL)洗涤。将合并的有机萃取物经Na2SO4干燥并在减压下浓缩。将粗产物(棕色油,14.8g)通过快速硅胶色谱法(240g盒,0%-100%EA/Hex)纯化。所需产物以长拖尾峰的形式洗脱。浓缩纯级分,得到呈深黄色油状的(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2-氟-2-甲基丙-1-胺(4.211g,17.0mmol)。
1H NMR(300MHz,CDCl3)δ1.10(d,J=6.3Hz,3H),1.34(dd,J=3.0,21.9Hz,6H),2.68-2.95(m,4H),3.02(sextet,J=6.6Hz,1H),7.05(d,J=2.4Hz,1H),7.26-7.11(m,2H),7.36(d,J=6.9Hz,1H),7.62(d,J=7.5Hz,1H),8.18(br s,1H)。19F NMR(282MHz,CDCl3)δ-144.2.m/z:ES+[M+H]+249.0。
化合物1的制备
将4-((1-丙基氮杂环丁烷-3-基)氧基)苯甲醛(0.096g,0.4mmol,1.3当量)添加至(R)-N-(1-(1H-吲哚-3-基)丙-2-基)-2-氟-2-甲基丙-1-胺(0.070g,0.3mmol,1.0当量)于无水甲苯(1.50mL)和冰醋酸(0.100mL,1.7mmol,6.2当量)中的溶液。添加分子筛并将溶液在N2下在黑暗中在80℃下搅拌8小时。将反应溶液在DCM中稀释,过滤,并用饱和Na2CO3溶液洗涤。将水层用DCM萃取,并将合并的有机层经Na2SO4干燥。将溶液过滤并浓缩。将残余物溶解于乙腈(2mL)中并通过注射器过滤器过滤,然后通过制备型LC(40%至90%ACN:H2O经18分钟,然后等度90%ACN持续7分钟)进行纯化。将纯级分浓缩并干燥,得到呈白色粉末的(1R,3R)-2-(2-氟-2-甲基丙基)-3-甲基-1-(4-((1-丙基氮杂环丁烷-3-基)氧基)苯基)-2,3,4,4a,9,9a-六氢-1H-吡啶并[3,4-b]吲哚。
实施例2
雌激素受体蛋白质水平测定
本实施例描述在多种细胞系中关于ERα蛋白水平评估多种化合物(ARN-810、AZD9496、化合物1、因多昔芬和氟维司群)。取决于细胞类型,将每孔90,000-500,000个细胞预先涂铺到12孔培养皿的每个孔中,并在含有5%木炭葡聚糖剥离胎牛血清(剥离FBS)(HyClone)的无酚红培养基中孵育至少24小时。将细胞在无血清培养基中用300nM抗雌激素处理4小时,随后将裂解物用补充有蛋白酶和磷酸酶抑制剂(ThermoFisher Scientific)的RIPA缓冲液裂解。将全蛋白质提取物在10%SDS-PAGE TGX凝胶上分离并转移至硝酸纤维素膜(BioRad)。将印迹与小鼠单克隆抗ERα,D12(#sc-8005,SantaCruzBiotechnology)或SP1(#MA5-14501,ThermoFisher Scientific)一起孵育。β-肌动蛋白单克隆抗体(#MA5-15739或#MA5-16410(ThermoFisher Scientific)或#sc-47778(SantaCruz Biotechnology))用作负载对照。将印迹与缀合至辣根过氧化物酶(ThermoFisher Scientific)的适当第二抗体一起孵育。使用Super Signal Femto化学发光试剂(ThermoFisher Scientific)检测信号。结果描绘于图2中。如可以看出,除因多昔芬以外的所有化合物都显示出显著降低大多数细胞系中的ER蛋白水平的能力;化合物1和氟维司群在降低ER蛋白水平方面最有效,并且在此方面显示相当的活性。
实施例3
细胞增殖测定
本实施例描述评估所测试化合物对人MCF-7细胞的影响的测定,所述细胞是人ER+乳腺癌细胞系。具体地,将每孔1000个MCF-7细胞(Cheryl Walker,Baylor College ofMedicine)图谱到含有5%剥离FBS的无酚红培养基(ThermoFisher Scientific)中的96孔板中。至少4小时后,将细胞用抗雌激素处理,并将培养基在100pM E2存在下稀释至2.5%剥离FBS,持续6-8天。使用CyQuant荧光DNA结合染料试剂盒(ThermoFisher Scientific)测量增殖,使用1:200GR染料并在485nm激发和538nm处读取荧光。
实施例4
雌激素受体和变体的瞬时转染
本实施例描述将某些雌激素受体构建体转染至Ishikawa细胞中的研究,所述Ishikawa细胞是人子宫内膜癌细胞系,测定了内源性碱性磷酸酶。将每孔15,000个Ishikawa细胞涂铺到含有5%剥离FBS的酚红培养基中的96孔板中。在涂铺时,使用Lipofectamine LTX(ThermoFisher Scientific)用75-100ng的雌激素受体构建体(或空载体,pSG5)瞬时转染每个孔中的细胞。大约4小时后,用所指示量的抗雌激素(不存在E2)或500pM E2(图9)处理细胞,并将培养基稀释至2.5%剥离FBS。将细胞孵育3天,除去培养基,并将板在-80℃下冷冻。将解冻的板与磷酸对硝基苯酯(ThermoFisher Scientific)一起孵育,磷酸对硝基苯酯是AP的发色底物并且因此揭示AP活性水平。在40℃下40-80分钟后,在405nm处读取吸光度。
化合物1具有ER拮抗剂而不是激动剂活性
如上所述测定未转染的Ishikawa细胞中内源性野生型ER的AP活性。将细胞用所指示的单独化合物(ARN-810、AZD-9496、化合物1、因多昔芬或氟维司群)处理(激动剂模式),或在500pM 17-雌二醇(E2)存在下(拮抗剂模式)处理。结果呈现在图1A(激动剂模式)和图1B(拮抗剂模式)中。可以看出,所有化合物都显示出有意义的拮抗剂活性,其中化合物1和氟维司群最有效。除化合物1和氟维司群外的所有化合物也显示出显著激动剂活性。
某些突变型ER增加配体非依赖性ER活性
如上所述,将野生型ER(HEGO)、空载体(pSG5)或所指示的LBD突变体ER瞬时转染到Ishikawa细胞中。仅空载体用500pM 17-雌二醇(E2)处理。72小时后,测定细胞的AP活性。结果呈现于图9中。条形表示来自一式三份孔的405nm处的平均吸光度+s.e.m.。可以看出,观察到各种测试的ER突变体是“激活突变体”,因为当配体不存在时,与野生型ER相比,它们显示出更多活性。
激活结构域1(AF1)为在某些ER突变体情况下观察到的配体非依赖性活性所需
AF1野生型ER(HEGO,AA 1-595)、空载体(pSG5)或缺失激活结构域2(“AF2”)(AA 1-282)或激活结构域1(“AF1”)(AA 178-595,有和没有Y537S突变)的所指示ER如上所述瞬时转染到Ishikawa细胞中。72小时后,测定细胞的AP活性。条形表示来自一式四份孔的在405nm处的平均吸光度+s.e.m.。可以看出,即使在激活Y537S突变(ΔAF1/Y5372)存在下,F1AF1也为在ER被截短(ΔAF2)时观察到的配体非依赖性ER活性所需。
化合物1抑制配体非依赖性ER突变体的活性
如上所述将野生型ER或所指示的ER变体瞬时转染到Ishikawa细胞中,并在化合物1或氟维司群存在下测定活性。结果呈现于图5A-5F中(图5A至5F中的每一个都报告特定细胞系,如每个图中所指示。点表示来自重复孔的针对媒介物归一化的平均AP活性+/-s.e.m.。使用最小二乘拟合方法拟合化合物1和氟维司群的剂量反应曲线,并使用可变斜率S形剂量反应模型计算pIC50(-Log IC50)。线表示(用空载体(pSG5)转染)的内源性受体的归一化AP活性。可以看出,化合物1以与氟维司群相当的IC50抑制配体非依赖性ER突变体中的每一者的活性。
某些临床候选物未能抑制配体非依赖性ER突变体的活性
如上所述将野生型ER或所指示的ER变体瞬时转染到Ishikawa细胞中,并在化合物1或氟维司群存在下测定活性,与因多昔芬、RAD-1901、ARN-810(GDC-0810)或AZD-9496进行比较(结果描绘在图8A-8B中,其中化合物1和氟维司群在图8A和8B中与因多昔芬和RAD-1901进行比较,或在图8C-8D中与ARN-810(GDC-0810)和AZD-9496进行比较。点表示来自一式三份孔的在405nm处的平均吸光度+s.e.m.。线表示(用空载体(pSG5)转染)的内源性受体的AP活性。可以看出,因多昔芬、RAD-1901、ARN-810(GDC-0810)或AZD-9496都不能如化合物1和氟维司群那样抑制配体非依赖性ER变体的活性。
Claims (30)
2.如权利要求2所述的方法,其中所述突变是激活突变。
3.一种治疗患有癌症的受试者的方法,所述方法包括施用作为雌激素受体的激活功能1和激活功能2两者的抑制剂的化合物。
5.一种治疗患有癌症的受试者的方法,所述方法包括施用作为激活功能2的抑制剂的化合物和作为激活功能1的抑制剂的第二剂。
7.如权利要求6所述的方法,其中所述化合物选自氟维司群和化合物1。
8.如权利要求7所述的方法,其中所述化合物是化合物1。
9.如权利要求8所述的方法,其中所述第二剂是CDK4/6抑制剂。
10.如权利要求9所述的方法,其中所述CDK4/6抑制剂选自帕博西尼、瑞博西尼、阿贝西尼、莱罗西尼和曲拉西尼。
11.如权利要求10所述的方法,其中所述CDK4/6抑制剂选自帕博西尼和阿贝西尼。
12.如权利要求9所述的方法,其中所述第二剂是PIK3CA抑制剂。
13.如权利要求12所述的方法,其中所述PIK3CA抑制剂选自阿培利司和他塞利司。
14.如权利要求9所述的方法,其中所述第二剂是mTOR抑制剂。
15.如权利要求14所述的方法,其中所述mTOR抑制剂选自西罗莫司、替西罗莫司和依维莫司。
18.如权利要求17所述的方法,其中向所述受试者施用的所述组合物的量是30mg/kg或更少。
19.如权利要求18所述的方法,其中向所述受试者施用的所述组合物的量是10mg/kg或更少。
20.如权利要求19所述的方法,其中向所述受试者施用的所述组合物的量是1mg/kg或更少。
21.如权利要求20所述的方法,其中向所述受试者施用的所述组合物的量是0.1mg/kg或更少。
22.如权利要求17-21中任一项所述的方法,其中每天一次向所述受试者施用所述组合物。
23.如权利要求17-21中任一项所述的方法,其中每周一次向所述受试者施用所述组合物。
24.如权利要求17-21中任一项所述的方法,其中每月一次向所述受试者施用所述组合物。
25.如权利要求17-24中任一项所述的方法,其中所述组合物呈单位剂型的形式。
26.如权利要求17-24中任一项所述的方法,其中所述组合物呈胶囊形式。
27.如权利要求17-24中任一项所述的方法,其中所述组合物呈片剂形式。
28.如权利要求17-24中任一项所述的方法,其中所述组合物呈溶液形式。
29.如权利要求17-24中任一项所述的方法,其中所述组合物呈悬浮液形式。
30.如权利要求1-29中任一项所述的方法,其中所述癌症是乳腺癌。
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