CN113272294A - 2,6-双(((1h-苯并[d]咪唑-2-基)硫)甲基)吡啶和n2,n6-二苄基吡啶-2,6-二甲酰胺衍生物以及相关化合物作为磷酸肌醇3-激酶(pi3k)抑制剂用于治疗癌症 - Google Patents
2,6-双(((1h-苯并[d]咪唑-2-基)硫)甲基)吡啶和n2,n6-二苄基吡啶-2,6-二甲酰胺衍生物以及相关化合物作为磷酸肌醇3-激酶(pi3k)抑制剂用于治疗癌症 Download PDFInfo
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- CN113272294A CN113272294A CN201980064325.7A CN201980064325A CN113272294A CN 113272294 A CN113272294 A CN 113272294A CN 201980064325 A CN201980064325 A CN 201980064325A CN 113272294 A CN113272294 A CN 113272294A
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Abstract
2,6‑双(((1H‑苯并[d]咪唑‑2‑基)硫)甲基)吡啶和N2,N6‑二苄基吡啶‑2,6‑二甲酰胺衍生物以及相关化合物作为磷酸肌醇3‑激酶(PI3K)抑制剂用于治疗癌症。本发明涉及药学活性的2,6‑双(((1H‑苯并[d]咪唑‑2‑基)硫)甲基)吡啶、N2,N6‑二苄基吡啶‑2,6‑二甲酰胺和N2,N6‑双(3‑羟苯基)吡啶‑2,6‑二甲酰胺,以及其衍生物,且涉及结构相关的化合物。这些化合物是磷酸肌醇3‑激酶抑制剂(PI3K)并且可用于治疗或预防癌性疾病。本发明进一步涉及制备这类化合物的方法以及包含此类化合物和任选地连同其他药学活性化合物的药物组合物和制剂。本发明进一步涉及测定PI3Kα或PI3Kα突变体的活性的方法,该方法包括:a)提供固相,该固相通过将GST‑GRP1分子固定在其上而被功能化,b)进行PI3Kα或PI3Kα突变体催化的酶反应以将PIP2转化为PIP3,c)加入带有可检测标记或报告分子的竞争者PIP3,以及d)基于步骤b)中获得的与竞争者PIP3竞争结合所述功能化固相的PIP3的量来确定酶活性。
Description
发明领域
本发明涉及可用于医药,特别是在哺乳动物中(优选在人类中)治疗或预防癌性疾病,特别是易感于磷酸肌醇3-激酶突变或由磷酸肌醇3-激酶突变引起的癌症疾病中的化合物。本发明进一步涉及包含此类化合物,任选地与其他药学活性化合物一起的药物组合物,以及包含此类化合物或药物组合物的药物制剂。本发明进一步公开了制备此类化合物的方法和测定磷酸肌醇3-激酶α或突变酶的活性的测定法。
背景技术
致癌作用是正常细胞转化为癌细胞的过程。它的特征是在细胞、遗传和表观遗传学水平上的变化进展,最终改变了细胞的程序使其经历不受控制的细胞***,从而大部分形成了恶性肿块。尽管已经公认致癌作用在很大程度上是癌基因的不规则活化和/或肿瘤抑制剂失活(导致各种病理变化)的结果,但是致癌作用的原因是多种多样的或未知的。此外,致癌作用途径涉及许多基因、因子和条件,它们本身及其相互作用仍然非常复杂或不清楚。因此,抗癌药物的开发很大程度上是基于反复试验的运气,而社会上仍然缺乏有效的抗癌药。
市场上大多数药物均设计为直接与其生物学靶标的主要活性位点(也称为正构位点)结合。变构调控剂相比正构调控剂具有重要的优势:它们的选择性可以更高,因为变构位点的保守性更低(Bagal等人,J.Med.Chem.,62:247-265(2019)),它们可以改变蛋白质水平或在细胞内的定位(Generoso等人,Nat.Chem.Biol.,11:280-286(2015)),改变蛋白质功能的细微方面(例如四级结构的形式或构象)(Zheng等人,J.Am.Chem.Soc.,140:5914-5924(2018);Shibayama等人,J.Biol.Chem.,292:18258-18269(2017)),并且在提供酶促活化的能力方面是独特的(Milne等人,Nature,450:712-716(2007))。此外,变构药物可以与正构配体协同性使用,该方法已成功用于预防癌症治疗中抗性的产生(Wylie等人Nature,543:733-737(2017))。变构可能也是由于缺乏已知的活性位点(例如KRAS)而被认为是无成药性的药物蛋白的关键。还可以通过构象特异性的变构抗体来达到变构靶向,这是未来研究的一个重要领域。已经有变构性靶向离子通道(Lee等人,Cell,157:1393-1404(2014)),GPCR(Mukund等人,J.Biol.Chem.,288:36168-36178(2013))以及细胞因子和整联蛋白受体(Rizk等人,Cell Commun.Signal.,13:1-5(2015);Schwarz等人Circ.Residual.,99:25-33(2006))的单克隆抗体的明显例子。重要的是,变构调控剂具有抵抗位于患者正构位点处的耐药性突变的潜力。例如,BCR-ABL1的“看门人突变”T315I导致对一组临床批准的正构药物(例如伊马替尼、博舒替尼(bosutinib)、尼洛替尼和达沙替尼)产生抗性。用与激酶C叶处的肉豆蔻酰基口袋结合的变构抑制剂ABL001(asciminib)治疗T315I突变体可以克服耐药性(Schoepfer等人,J Med Chem 61:8120-8135(2018);Wylie等人,Nature,543:733-737(2017))。
迄今为止,变构结合位点和靶向那些位点的先导化合物的发现大多是偶然的,是通过高通量筛选以及随后对作用机制的后续实验工作实现的。当前缺乏合适的理论背景来解释不同蛋白质类别中的变构、实验数据和能够实施此药物设计策略的模拟技术,从而导致变构候选药物的开发成本很高,尽管在过去十年中,大量的蛋白质结构数据已经很容易获得,包括许多膜蛋白类别(例如GPCR和离子通道),它们是常见的变构药物靶标,同时改进的模拟方法现在更好地提供了对变构机制关键性的蛋白质动力学和协同运动的原子了解。
PI3K–AKT–mTOR是乳腺癌中最频繁激活的信号传导途径(Miller等人,BreastCancer Res,13:224(2011)),并已在III期临床试验中被确认为治疗靶标(André等人,Lancet Oncol 15:267-274(2014))。此外,在下调时变得重点参与结肠、乳腺和子宫内膜的肿瘤发生的信号传导途径之一受到磷酸肌醇-3'-激酶α(PI3Kα)的作用,其为四种PI3K同等型中的一种(Engelman等人,Nat Rev Genet 7:606-619(2006);Massacesi等人,OncoTargets Ther 9:203–210(2016))。PI3Kα由催化亚基p110α(由PIK3CA基因编码)和调节亚基p85α(由PIK3R1基因编码)组成。PI3Kα途径的失调长期以来一直与癌症发展关联,但是直到最近十年才发现PIK3CA中普遍发生的突变是致癌的(Liu P等人,Nat Rev Drug Disc,8:627-644(2009))。
PIK3CA在多种癌症中突变,在乳腺癌中的突变发生最为明显,其中PIK3CA是突变频率最高的癌基因,平均约27%的病例具有遗传变异,子宫内膜癌中有24%的病例,而在结肠癌中有约15%的病例具有遗传变异(Liu P等人,Nat Rev Drug Disc,8:627-644(2009))。PIK3CA突变见于多种癌症中,更具体地是:乳腺癌,结肠癌,子宫内膜癌,脑肿瘤,皮肤癌,卵巢癌,胃癌,肺癌,甲状腺癌,头颈癌,***,胰腺癌,肝/胆道癌,垂体瘤,泌尿道肿瘤,白血病/淋巴瘤,神经母细胞瘤(Samuels和Waldman,Curr Top Microbiol Immunol,347:21-41(2010))。这些突变中的80%导致位于两个热点中任一个中的氨基酸置换:(a)在PI3Kα的螺旋结构域中,最常见的置换是外显子9中的Lys取代Glu(E545K),(b)在激酶结构域中,外显子20中His被改变成Arg(H1047R)(Miled等人,Science 317:239-42(2007))。这两种类型的突变均增加了酶的激酶活性,上调了下游AKT途径和VEGF信号传导,并刺激了细胞转化、肿瘤发生和血管生成(Samuels等人,Cancer Cell 7:561-572(2005);ParsonsClin Cancer Res 11:7965-7966(2005),Hu等人,Clin Cancer Res 11:8208-8212(2005)。带有H1047R突变的人类癌症列表可以在Thorpe等人,Nat Rev Cancer 15(1):7-24(2015)以及Samuels和Waldmann,Curr Top Microbiol Immunol 347:21-41(2010)中找到。
PI3K途径牵涉到与对化学疗法、放射疗法、激素疗法和靶向药剂的抗性(Massacesi等人,Onco Targets Ther 9:203-210(2016))。因此,当作为组合疗法的一部分施用时,PI3K抑制剂可以恢复对癌症治疗的敏感性(Burris HA III,Cancer ChemotherPharmacol.71:829-842(2013))。
目前,许多PI3K抑制剂正在临床研究中,包括靶向I类PI3K的所有四种同等型的泛PI3K抑制剂,以及PI3Kα选择性抑制剂alpelisib(BYL719),该药物正处于用于患有进展的晚期乳腺癌的绝经后女性的III期临床试验中(Dienstmann等人,Mol Cancer Ther 13(5):1021-1031(2014);https://clinicaltrials.gov/ct2/show/NCT02437318)。在早期的临床研究中,alpelisib表现出良好的耐受性概况,其不良事件与对PI3K的“在靶”抑制相一致(Massacesi等人,Onco Targets Ther 9:203-210(2016))。
2019年5月24日,alpelisib作为第一个PI3K抑制剂获得FDA批准用于治疗激素受体(HR)阳性、人表皮生长因子受体2(HER2)阴性、PIK3CA突变的晚期或转移性乳腺癌,与氟维司群联合治疗,用于绝经后女性和男性患者。为了启动alpelisib治疗,需要通过FDA批准的诊断测试来确认组织和/或液体活检样品收集物中存在PIK3CA突变。Alpelisib是PI3Kα活性位点的抑制剂,其利用PI3Kβ、γ和δ同等型的活性位点之间的差异来实现其特异性。然而,alpelisib是PI3Kα活性位点的抑制剂,其中Gerspacher等人,Bioorg Med Chem Lett.;25:3582-4(2015)将BYL719(341)的5-(吡啶-4-基)噻唑-2-氨基双环核心支架转变成新的4H-噻唑[5’,4’:4,5]吡喃并[2,3-c]吡啶三环支架(342),经由氧作为接头。活性结果显示,与BYL719的非环化类似物(341,PI3Kα/β/δ/γIC50=5/1200/290/250nM)相比,343(PI3Kα/β/δ/γIC50=5/670/220/200nM)表现出相似或更好的生化效能、对PI3Ka的选择性和细胞活性,以及由于增加的溶解度而具有良好的药代动力学性质。与强效和选择性抑制剂alpelisib(BYL719)结合的p110a的晶体结构已发表在(Furet等人,Bioorg Med ChemLett.;23(13):3741-8(2013))中。对于所有图,铰链残基和抑制剂之间的酰胺氢键均以红色显示。该氢键模拟在ATP的腺嘌呤环与激酶结构域的铰链区之间形成的氢键。对p110a的高于对其他PI激酶的特异性主要是由BYL719与非保守的p110a残基Q859可形成的独特氢键相互作用驱动的。
靶向PI3K途径的一个关键挑战是鉴定同等型选择性的抑制剂,因为四种PI3K同等型参与不同的细胞过程,包括葡萄糖稳态和免疫应答(Knight等人,Cell 125:733-747(2006))。四种PI3K同等型在三磷酸腺苷(ATP)结合口袋中的高度相似性经常导致开发的是非选择性PI3K候选药物,这可能会产生不想要的副作用。靶向患者中的单一PI3K同等型可以允许以不受与抑制多种同等型有关的毒性限制的治疗剂量进行施用。尽管alpelisib已达到一定程度的有力的选择性,但活性位点容易发生突变,最终导致耐药性。变构调控剂提供了用于选择性激酶抑制的新方法,因为它们靶向与活性位点相比保守性较低的结合位点;因此,可以获得更高的选择性(Changeux,Drug Disc Today 10:e223-228(2013))。
因此,在本领域中仍然需要能够预防或抑制哺乳动物,特别是人类中的肿瘤生长的有效和选择性的治疗剂。
人(Huang等人,Science 318:1744-1748(2007))和小鼠(Hon等人,Oncogene 31:3655-3666(2012))催化亚基p110α的3D结构以及人H1047RPI3Kα突变体的结构(Mandelker等人,Proc Natl Acad Sci USA 106:16996-17001(2009))已通过X射线晶体学解析。最近的实验数据表明,H1047RPI3Kα突变通过诱导激酶结构域中的动态变化而过度激活该酶,这增加了基础ATPase活性并暴露了膜结合区,从而增强了基底膜结合(Huang等人,Science318:1744-1748(2007);Mandelker等人,Proc Natl Acad Sci USA106:16996-17001(2009))。
发明人已经开发了具有极高特异性的先进的靶向治疗方法,其利用突变体和野生型PI3Kα蛋白的不同结构特征来设计新型抑制剂。发明人的最近研究表明,通过考虑野生型(WT)和突变蛋白之间的动力学和结构差异,可以选择性地靶向H1047R突变的PI3Kα(Gkeka等人,PLoS Comput Biol 10:e1003895(2014);Lionta等人,Curr Top Med Chem 14:1923-1938(2014);Gkeka等人,J Phys Chem B 119:1002-1016(2015))。这些研究用于鉴定新的结合口袋和设计突变体特异性的PI3Kα抑制剂以利用改变的突变体构象。最近的晶体结构(Hon等人,Oncogene 31:3655-66(2012))证实了已知的PI3K抑制剂PIK-108在鉴定出的一个结合口袋中的结合。将先进的计算和数学技术与体外实验结合使用,发明人表明与该特异性结合口袋的结合不会诱导对PI3Kα的任何变构作用(Gkeka等人,J Phys Chem B 119:1002-1016(2015)。他们进一步研究了突变位点附近的其他结合口袋,并检查了与之结合的化合物是否可能充当变构抑制剂,即通过结合蛋白活性位点以外的位点来调节蛋白。
该方法旨在通过使用小分子抑制剂来治疗癌症,所述小分子抑制剂仅对PIK3CA的致癌突变体形式起作用且对野生型蛋白具有选择性。本发明采用了一系列的计算机、合理药物设计,有机合成,生化体外测定和在异种移植物和基因修饰的小鼠模型中的体内研究。
最初,使用分子动力学模拟对WT和H1047R突变体PI3Kα的全长催化p110α亚基建模。使用来自该模拟的数据,计算了PI3KαWT蛋白和突变体H1047R的代表性构象。这些构象被进一步利用以鉴定用于选择性抑制突变体蛋白的变构口袋(Gkeka等人,PLoSComputBiol 10:e1003895(2014);Gkeka等人,J Phys Chem B 119:1002-1016(2015))。使用位置协方差矩阵来确认所鉴定的结合位点与PI3Kα的活性(ATP)位点的变构通讯,发明人用该矩阵测量了每个所鉴定的结合位点与活性PI3Kα位点的残基之间的运动相关性。活性位点附近的一个空腔被证实是变构的,并进一步用于计算机辅助药物的从头设计中。随后对毒性、样式可行性、化学多样性和理化特性打分最高的化合物进行后处理,从而鉴定出了最初的先导化合物并合成了几种它的类似物。
使用含有PIP2的脂质体对鉴定出的先导化合物及其类似物进行PI3Kα活性测定(Gkeka等人,PLoSComput Biol 10:e1003895(2014))。PIK3CA(WT或H10147R)/PIK3R1的复合物获自Millipore。该测定基于Millipore提供的方案,并进行了修改(Papafotika等人,准备中),其将在下面进一步描述。在此测定法中,PI3Kα产生的PIP3分子与生物素化的PIP3竞争以结合重组GST-GRP1-PH结构域(氨基酸263-380),该结构域在细菌中产生,与谷胱甘肽包被的96孔板结合。通过结合板的链霉亲和素-HRP的过氧化物酶活性来估算生物素-PIP3的竞争量的定量,并为蛋白质的活性提供了一种量度。将化合物与测定混合物的所有组分(PIP2除外)在25℃预孵育10分钟。在预孵育期结束时添加PIP2,从而启动激酶反应。使用logit-log图从剂量-应答曲线计算IC50值。所有测定均在至少三个独立的实验中进行,每个浓度一式三份。PIK-108和渥曼青霉素用作对照(Gkeka等人,J Phys Chem B 119:1002-1016(2015))。
异种移植物是癌症的体内模型,其中将来自癌细胞系的细胞植入免疫缺陷小鼠中。异种移植物模型用于创建允许癌症自然生长,对其进行监测和相应治疗评估的环境。在本文中,发明人使用在皮下注射来自乳腺癌细胞系MDA-MB-231(为野生型PIK3CA)和乳腺癌细胞系HCC1954(带有PIK3CA上外显子20的H1047R突变)的细胞后具有异位异种移植物的免疫缺陷(SCID)小鼠。
为了测试潜在的抗癌药物的体内活性,需要建立相应的癌症动物模型。为了在选定的解剖部位产生小鼠肿瘤,经常使用基于Cre/loxP重组的遗传方案的变体。根据驱动Cre表达的启动子的组织特异性,相应的肿瘤会在Cre产生者小鼠和携带休眠的致癌转基因的Cre反应者伴侣之间交配衍生的后代中形成,该休眠的致癌转基因在切除上游定位的阻止其表达的flox修饰的DNA片段后可发挥功能[参见Politi等人Oncogene 23:1558-1565(2004);Klinakis等人Proc Natl Acad Sci U S A S 106:2359-2364(2009),Stratikopoulos等人Cancer Cell27:837-851(2015))。为了开发携带Pik3ca获得功能突变(以下称为Pik3ca*)的小鼠品系,遵循了敲入基因靶向策略(Stratikopoulos等人.CancerCell 27:837-851(2015))。因此,靶向Pik3ca基因座的两个热点突变中的任何一个(外显子20或外显子9中),以便突变的Pik3ca将从内源性基因座表达,而不是从转基因表达,从而模仿在人类肿瘤中发现的表达。将动物与WAPCre产生者交配后实现了外显子20Pik3ca致癌突变的激活(WAP是一种乳蛋白,其启动子用于驱动Cre表达,特别是在乳腺中)。经过非常长的490天(中位数)的潜伏期后,此类动物出现了乳腺肿瘤。但是,将WAPCre/外显子20Pik3ca*与表达MMTV-Myc的小鼠(其本身会在5-7个月形成乳腺肿瘤)交配,在具有基因型WAPCre/外显子20Pik3ca*/MMTV-Myc的分娩的雌性小鼠中观察到肿瘤的出现加速(分娩后1周)。将这些小鼠用于测试本文讨论的化合物的功效。
本发明的一个目的是基于在体外生化测定法和非人转基因动物模型中证明的相关生物学活性,鉴定适用于治疗或预防哺乳动物中癌性疾病的化合物。本发明的另一个目的是提供可用于治疗或预防哺乳动物中的癌性疾病的化合物和组合物,以及涉及对需要这种治疗的哺乳动物施用治疗有效量的此类化合物的治疗方法。
发明内容
本发明总体上涉及具有取代的苄基或吡啶骨架的化合物。特别地,本发明的一个方面涉及式(I)的化合物:
其互变异构体,多晶型物,水合物,溶剂合物,代谢物,前药或其药学上可接受的盐,其中
L独立地为H或OH;
X独立地为N或C;
Y独立地为H或=O;
Z独立地为S或NH;
R1独立地为单环或多环芳基、杂芳基或环烷基,包括但不限于以下实例:
R2独立地是羟基,氢,氟,氯或溴中的至少一种;和
Y1独立地为C,O,S,NH或N,其中Y1为O、S和NH的定义优选适用于五元芳族环系,而Y1为N的定义优选适用于六元环。
在上述定义和本说明书其他地方所包含的定义的上下文中,R2作为取代基也可以不存在,即它的存在是任选的。此外,取决于确切的化学结构,式中可以包括羟基,氢,氟,氯或溴取代基中的多于一种作为取代基。
特别地,本发明提供了上述物质用于医药,特别是用于治疗或预防癌性疾病,特别是易感于PI3Kα突变和/或过度活化和/或扩增和/或失调,或由其引起或触发的癌性疾病。
在一个优选的实施方案中,式(I)是指具有以下式(II)的化合物:
或其药学上可接受的盐。该化合物在本文中也以其内部名称PI3K-010来指代。
在另一个优选的实施方案中,式(I)是指具有以下式(III)的化合物:
或其药学上可接受的盐。该化合物在本文中也以其内部名称PI3K-021来指代。
在另一个优选的实施方案中,式(I)是指具有以下式(IV)的化合物:
或其药学上可接受的盐。该化合物在本文中也以其内部名称PI3K-024来指代。
在另一方面,本发明还涉及包含一种或多种如上定义的式(I)的化合物,以及优选地化合物II和/或III的药物组合物。任选地,所述药物组合物可以进一步包含一种或多种其他的治疗剂,例如另外的或已知的抗癌剂。再次,特别地,本发明涉及所述药物组合物用于治疗或预防癌性疾病,特别是易感于PI3Kα突变和/或过度活化和/或扩增和/或失调,或由其触发的癌性疾病。
在某些实施方案中,上述药物组合物可以进一步包含一种或多种另外的治疗剂,例如COX-2加氧酶抑制剂。
在本发明的另一方面,本文所指的化合物或药物组合物旨在用于医学中。优选地,所述化合物或药物组合物用于治疗或预防哺乳动物中癌性疾病的方法。优选地,哺乳动物是人类。
在一些实施方案中,所述化合物或药物组合物用于治疗易感于PI3Kα突变和/或失调或由其引起、触发、或加重的癌性疾病的方法。
本发明的另一方面涉及用于制造上述式(I)的化合物的方法:
其中所述方法包括首先合成具有通式(V)的氯化物:
其中X,L,Y如上所定义,然后与如上式(I)所定义的模块R1-Z-H反应,得到如上所示的式(I)化合物。
本发明的另一方面涉及在竞争性免疫测定中测定PI3Kα或PI3Kα突变体活性的测定法。
附图说明
图1.体外PI3Kα活性测定表明PI3K-010对H1047R PI3Kα的11倍选择性。使用SigmaPlot的logit-log图和线性回归分析估计IC50。误差条显示了来自至少三个独立实验的均值的标准误差,每个实验一式三份进行。
图2.测试ATP和PI3K-010之间对PI3Kα活性位点的竞争的实验结果。使用100μMATP的标准浓度(上图)和ATP的高20倍浓度(下图)在浓度增加的PI3K-010下测定PI3Kα的活性。使用SigmaPlot的logit-log图和线性回归分析估计IC50。误差条显示了来自至少三个独立实验的均值的标准误差,每个实验一式三份进行。在存在高ATP浓度的情况下,PI3K-010的IC50没有显著改变,表明该化合物是PI3Kα的非竞争性抑制剂。
图3.体外PI3Kα活性测定例示了PI3K-021对H1047R PI3Kα的选择性。使用SigmaPlot的logit-log图和线性回归分析估算PI3K-021对突变H1047R PI3Kα的IC50。误差条显示了来自至少三个独立实验的均值的标准误差,每个实验一式三份进行。通过外推估计对于WT PI3Kα的IC50。
图4.PI3K-024对WT和H1047R PI3Kα的的体外PI3Kα活性测定。PI3K-024对突变体H1047R的IC50为64nM,对WT PI3Kα的IC50为6nM。这些值是使用SigmaPlot的logit-log图和线性回归分析估算的。误差条显示了来自至少三个独立实验的均值的标准误差,每个实验一式三份进行。
图5.PI3K-010或PI3K-021对通过异位移植人类乳腺癌细胞系MDA-MB-231细胞系(为野生型PIK3CA)和乳腺癌细胞系HCC1954(带有PIK3CA突变H1047R)产生的异种移植物进行治疗的结果。
图6.在用PI3K-010化合物治疗乳腺癌的开始和结束时(一个月),WAPCre/外显子20Pik3ca*/MMTV-Myc小鼠(与阴性野生型对照相比)的微型PET/CT成像的示例。
图7.PI3K激酶活性测定原理的示意图。在该测定中,首先将GST-GRP1与谷胱甘肽包被的板孵育。然后,GST-GRP1与生物素标记的PIP3形成稳定的复合物,然后使用链霉亲和素-HRP缀合物并用OPD在492nm处读数进行定量。当PI3Kα磷酸化PIP2时生成的未标记的PIP3与标记的b-PIP3竞争结合GRP1的PH结构域,从而导致492nm处的信号减少。
图8:最佳量的GST-GRP1(PH结构域)的产生和滴定
a.GST-GRP1PH结构域在大肠杆菌菌株(DE3)中表达,并使用制造商的标准方案在谷胱甘肽-琼脂糖4B(Amersham Pharmacia)上亲和纯化。通过SDS-PAGE测定蛋白质的纯度。
b.将增加量的GST-GRP1PH结构域与谷胱甘肽包被的板一起孵育,然后先与生物素-PIP3(b-PIP3)孵育再与链霉亲和素-HRP孵育。HRP的量(反映结合的生物素-PIP3的量)是通过将板与Opposition Division(HRP的底物)一起孵育,然后测量492nm的吸光度来测量的。
图9:b-PIP3的滴定。将不同量的b-PIP3添加到谷胱甘肽包被的板(在该板上预结合有GST-GRP1),然后与链霉亲和素-HRP和Opposition Division连续孵育,接着测量492nm处的吸光度。选择0.3ng bPIP3的量用于后续测定,因为该试剂的量应足够高以偶联大部分可用的GST-GRP1并提供高信号,但又不应过大,因为这将需要更大的量的PI3K和PIP2用于测定法混合物中的竞争,这会增加化合物库筛选的成本。
图10:底物PIP2与b-PIP3竞争结合GRP1:
a.当将单独的长侧链PIP2与板一起孵育时,信号减少,这可能是由于PIP2和bPIP3之间竞争对GRP1的结合所致。
b.将板与含有PIP2的脂质体(使用已分离的HCT116细胞的脂质制备)一起孵育导致对生物素-PIP3信号的抑制大大降低,这表明将PIP2掺入脂质体降低其与GRP1的结合。在脂质体中包含50%PIP2的样品(尽管存在脂质体我们仍观察到信号的抑制)中,通过添加低浓度(低于CMC)的脱氧胆酸钠在酶促反应结束时显著恢复了信号,这导致信号的进一步恢复。
图11a:鉴定优选的底物制备物。使用2.5或5ng PI3K测试酶促反应。测试的底物是浓度为10%或50%PIP2脂质体的200ng PIP2,或2μg可溶性PIP2。注意,最有利的底物制备物是脂质体中50%PIP2的混合物。
图11b:底物的滴定。使用两种不同量的PI3K(2和4ng)一起测试了增加浓度的PIP2。底物(PIP2)以脂质体中50%浓度供应。
图12:标准曲线:吸光度对外源添加的PIP3。标准曲线遵循预测的竞争抑制的典型双曲线概况,其预期是酶促生产的PIP3和b-PIP3之间对结合GST-GRP1的竞争。
图13:对测定法的特异性的验证。
a.使用200ng PIP2(以脂质体中50%的浓度),指定量的PI3K,ATP和缓冲液组装酶促反应,并在25℃孵育16分钟。
b.显示了4、8、16、32和60分钟的孵育时间的时间依赖性。
图14:对测定法的特异性的验证。使用本发明的测定法确定已知PI3Kα抑制剂的IC50值。三种已知的PI3Kα抑制剂的IC50评估值与先前报道的值一致。
具体实施方式
定义
本申请中使用的所有术语应具有本领域相关技术人员,例如药物化学家,有机化学家,药剂师,分子生物学家,医师或其团队通常采用的含义。通过示例的方式,下面给出了一些特定术语的定义:
冠词“一”和“一个/一种”用于指代该冠词的语法对象中的一个或多个(即,至少一个/一种)。例如,“一个/一种细胞”是指一个/一种细胞,或多于一个/一种的细胞。
“金刚烷基”是指以“扶手椅”构型排列在三个连接的环己烷环中的环状不饱和脂族烃基基团。
“烷基”包括一价饱和脂族烃基基团。烃链可以是直链或支链的。
“芳基”是指衍生自芳环的任何官能团或取代基,例如苯基、萘基、噻吩基或吲哚基。在优选的实施方案中,芳基为取代或未取代的苯基、吡啶基或嘧啶基,更优选为苯基或吡啶基,甚至更优选为苯基。取代可以是在烃的母链上取代氢原子的原子或分子。合适的取代基是化学领域的技术人员,更具体地医药或有机化学领域的技术人员已知的。
“癌症”或“肿瘤”是指具有致癌细胞典型特征的细胞的存在,所述特征例如不受控制的增殖、永生化、转移潜力、快速生长和增殖速率、以及某些特征性的形态特征。癌细胞经常为肿瘤形式,但是这类细胞可以在动物中单独存在,或者可以是非致瘤性癌细胞,例如白血病细胞。如本文所用,术语“癌症”包括恶性前以及恶性的癌症。“癌性疾病”或“癌症”在本文可互换使用,其包括但不限于急性单核细胞白血病,急性髓性白血病,急性骨髓单核细胞白血病,急性早幼粒细胞性白血病,成人T细胞白血病,成人T细胞淋巴瘤,星形细胞瘤,非典型类癌肺癌,基底细胞癌,B急性淋巴细胞白血病,B细胞急性淋巴母细胞白血病/淋巴瘤,膀胱癌,脑癌,乳腺癌,支气管癌,伯基特氏淋巴瘤,胆管癌,原发性来源不明的癌症,***,慢性骨髓增生性病症,结肠癌,弥漫性大细胞淋巴瘤,子宫内膜癌,室管膜瘤,食道癌,胃癌,胶质瘤,胶质母细胞瘤,头颈癌,血管外皮细胞瘤,肝细胞癌,霍奇金氏淋巴瘤,卡波济肉瘤,肾癌,大细胞神经内分泌癌,大颗粒淋巴细胞性白血病,白血病,肝癌,肺癌,淋巴瘤,髓母细胞瘤,黑色素瘤,多发性骨髓瘤,骨髓增生异常综合征,鼻咽癌,神经母细胞瘤,NK细胞肿瘤,非霍奇金氏淋巴瘤,食管鳞状细胞癌,骨肉瘤,卵巢癌,胰腺癌,外周性T细胞白血病,原发性浆细胞白血病,***癌,肾透明细胞癌,视网膜母细胞瘤,横纹肌肉瘤,肉瘤,小细胞肺癌,T细胞急性淋巴母细胞性白血病,T细胞急性淋巴母细胞性淋巴瘤,睾丸癌,胸腺瘤,甲状腺癌,脐尿管癌,子宫癌,***癌等。
“环烷基”是指环状饱和脂族烃基基团。与给定的环烷基基团相关提及的C原子的数目对应于形成环的碳原子的数目,例如“C6环烷基”是指环己基。优选地,本文提及的环烷基为C6-C14环烷基。
“环烯基”是指环状不饱和脂族烃基基团。与给定的环烯基基团相关提及的C原子的数目对应于形成环的碳原子的数目,例如“C6环烯基”是指环己烯基。在一些实施方案中,环烯基包含一个双键。在一些实施方案中,环己烯基包含超过一个双键,优选两个双键。
“失调”是指编码生物合成途径中酶/蛋白质的基因的表达的改变或修饰,使得所述酶/蛋白质的水平或活性被改变或修饰,其见于但不限于癌细胞。
“呋喃基”包含可以被任何C原子结合的呋喃环。
“卤代”或“卤素”是指氟,氯,溴和碘。优选的卤代基团是氟或氯。
“卤代烷基”包括进一步如上定义的“烷基”基团,其被一个或多个可以相同或不同的卤素取代。
“水合物”是指一种晶体形式,其保留一定数目的水分子作为固体晶体结构的一部分。
“赘生物”是指由于细胞异常生长或***而导致的异常组织块。其通常引起肿块或肿瘤。赘生物可能是良性、恶性前(原位癌)或恶性(癌)。
“过表达”是指基因的过度表达,从而产生其作用或产物的过量。大多数癌症是经由关键的细胞调节基因的过表达而引起的。
“前药”是指最初以非活性(或低于完全活性)形式向身体给药,然后通过身体的正常代谢过程转变成其活性形式的药物。
“吡唑基”包含可以被任何C原子及其氮原子结合的吡唑环。
“吡咯基”包含可被任何C原子及其氮原子结合的吡咯环。
“溶剂合物”是指一种晶体形式,其保留一定数目的水以外的溶剂分子作为固体晶体结构的一部分。
“互变异构体”是指有机化合物的组成性异构体,其通过称为互变异构的化学反应而容易地相互转化,该化学反应通常导致氢原子或质子的形式迁移,并伴随着单键和相邻双键的切换。
“苯硫基(thiophenyl)”包含可以被任何C原子结合的噻吩环。
任何“烷基”,“环烷基”,“呋喃基”,“吡咯基”,“苯硫基”,“芳基”或“苯基”可以未被取代或被一个或多个原子或原子组(分子)取代。
“药学上可接受的”是指当以药物剂型通常采用的剂量使用时,没有实质性的毒性作用,从而可以被批准或优选地被联邦或州政府的监管机构批准或列入美国药典或其他一般公认的药典可用于动物,更优选用于人类。
“药学上可接受的盐”是指本发明化合物的盐,其是药学上可接受的并且具有母体化合物的所需药理学活性。这类盐包括:(1)与无机酸形成的酸加成盐,所述无机酸如盐酸,氢溴酸,硫酸,硝酸,磷酸等;或与有机酸形成的酸加成盐,所述有机酸如乙酸,丙酸,己酸,环戊烷丙酸,乙醇酸,丙酮酸,乳酸,丙二酸,琥珀酸,苹果酸,马来酸,延胡索酸,酒石酸,柠檬酸,苯甲酸,3-(4-羟基苯甲酰基)苯甲酸,肉桂酸,扁桃酸,甲磺酸,乙磺酸,1,2-乙二磺酸,2-羟基乙磺酸,苯磺酸,4-氯苯磺酸,2萘磺酸,4-甲苯磺酸,樟脑磺酸,4甲基双环[2.2.2]-辛-2-烯-1-羧酸,葡庚糖酸,3-苯基丙酸,三甲基乙酸,叔丁基乙酸,月桂基硫酸,葡萄糖酸,谷氨酸,羟萘甲酸,水杨酸,硬脂酸,粘康酸等;或(2)当母体化合物中存在的酸性质子被替换时形成的盐,其中与带有正电荷的碱部分形成离子对。
“药学上可接受的载体”是指与本发明化合物一起施用的稀释剂,佐剂,赋形剂或载体。
“多晶型物”是指同一化合物的不同晶体形式。同质多晶表示材料以超过一种形式或晶体结构存在的能力。
“预防”或“防止”是指降低获得疾病或病症的风险(即,使得该疾病的至少一种临床症状不在受试者中发展,该受试者可能暴露于或易患该疾病但尚未经历或未显示出该疾病的症状)。
“治疗有效量”是指当施用于受试者以治疗疾病时足以对疾病实现此类治疗的化合物的量。“治疗有效量”可以根据化合物,疾病及其严重程度,以及要治疗的受试者的年龄,体重等而变化。优选地,根据本发明的化合物可以以0.1至200mg/kg的剂量使用,更优选以0.5至50.0mg/kg的剂量使用,优选这样的剂量每天应用两次。要施用的每日剂量也可以是50mg至500mg/天,优选150至300mg/天。无论如何,合适的剂量将由本领域技术人员通过在打算治疗的物种中或基于患者的应答进行的合适的常规给药实验来确定。合适的剂量可以在单次治疗中应用,或通过在几个不同的时间点应用合适的部分剂量来应用。
在一个实施方案中,“治疗”或“处理”任何疾病或病症是指改善该疾病或病症(即,阻止或减少该疾病或其至少一种临床症状的发展)。在另一个实施方案中,“治疗”或“处理”是指改善受试者可能无法辨别的至少一个体格参数。在又一个实施方案中,“治疗”或“处理”是指身体上地(例如,可辨别的症状的稳定),生理上地(例如,体格参数的稳定)或两者来调节疾病或病症。在再一个实施方案中,“治疗”或“处理”是指延迟疾病或病症的发作。
化合物和药物组合物
由于发明人的深入研究和创造性努力,他们成功创建了首次报道的PI3Kα突变体的变构抑制剂。
因此,本发明的一个方面涉及式(I)的化合物
其互变异构体,多晶型物,水合物,溶剂合物,代谢物,前药或药学上可接受的盐,其中
L独立地为H或OH;
X独立地为N或C;
Y独立地为H或=O;
Z独立地为S或NH;
R1独立地为单环或多环芳基,杂芳基或环烷基,包括但不限于以下实例:
R2独立地是羟基,氢,氟,氯或溴中的至少一种;
Y1独立地为C,O,S,NH或N,其中Y1为O、S和NH的定义优选应用于五元芳族环系,而Y1为N的定义优选应用于六元环。
优选地,该方面涉及式(I)化合物用于医药,特别是用于治疗癌性疾病。本发明人已经发现,式(I)的化合物是PI3Kα活性的同等型特异性的异位调控剂,并且至少降低或甚至完全抑制了与某些癌性疾病有关的PI3Kα突变体的活性,例如通过参与其发展和/或协助或促进其持续性和/或恶化。不希望受任何理论的束缚,已经发现所述化合物通过在不同于ATP的正构结合口袋的位点结合来变构性抑制突变体蛋白的活性,特别是热点突变体H1047R的活性。化合物与突变的Pl3Kα的变构结合会导致构象变化,从而影响PI3Kα突变体的催化活性并与ATP结合无关,因此影响突变体的活性。
在优选的实施方案中,式(I)是指具有式(II)的化合物:
或其药学上可接受的盐。该化合物在本文中也以其内部名称PI3K-010来指代。
在优选的实施方案中,式(I)是指具有式(III)的化合物:
或其药学上可接受的盐。该化合物在本文中也以其内部名称PI3K-021来指代。
在优选的实施方案中,式(I)是指具有式(IV)的化合物:
或其药学上可接受的盐。该化合物在本文中也以其内部名称PI3K-024来指代。
药物组合物
本发明还涉及包含如上所述的式(I)或优选地式(II)或式(III)或式(IV)的化合物的药物组合物。在本发明这一方面的一个优选的实施方案中,药物组合物中包括的式(I)化合物不包括化合物(IV),即,定义化合物(IV)的式(I)变体的定义不包括在该实施方案中。
任选地,本发明的药物组合物可以进一步包含一种或多种另外的治疗(即,药学活性)剂。
在一些实施方案中,药物组合物中的一种或多种其他治疗剂可以选自下组(A):10-羟基喜树碱,17-烯丙基氨基-格尔德霉素,2-甲氧基抗霉素A3,3,4-二氯异香豆素,4-羟基苯基视黄酰胺(Hydroxyphenylretinamide),9-顺式视黄酸,阿比特龙(Abiraterone),曲妥珠单抗美坦(Ado-Trastuzumab Emtansine),阿霉素,阿法替尼(Afatinib),N-(3-氯苯基)-6,7-二甲氧基喹唑啉-4-胺,2-氨基-4-(1H-吲哚-5-基)-1,1,3-三氰基丁-1,3-二烯,阿地白介素,阿仑单抗(Alemtuzumab),氨磷汀,阿那曲唑(Anastrozole),茴香霉素,阿非迪霉素(Aphidicolin),三氧化二砷,天冬酰胺酶菊欧文氏杆菌(Erwinia chrysanthemi),阿瓦斯汀,阿昔替尼(Axitinib),N-[2(S)-(2(R)-2-氨基-3-巯基丙基氨基)-3-甲基丁基]-L-苯丙氨酰-L-蛋氨酸三氟乙酸盐,卡介苗(Bacillus Calmette-Guerin),双酚A二缩水甘油醚,苯达莫司汀,β-拉帕醌,桦木酸,贝伐单抗,贝沙罗汀(Bexarotene),比卡鲁胺(Bicalutamide),双苯甲酰亚胺,博来霉素,硼替佐米,博舒替尼(Bosutinib),布舍瑞林(Buserelin),白消安,卡巴他赛,卡博替尼-S-苹果酸,Calpeptin,喜树碱,咖啡酸苯乙酯,卡培他滨,卡普雷萨(凡德他尼(Vandetanib)),卡铂,卡铂,卡非佐米,卡莫司汀,西妥昔单抗,苯丁酸氮芥,环格列酮(Ciglitazone),顺铂,氯膦酸盐,氯法拉滨,卡博替尼(Cometriq),克唑替尼(Crizotinib),姜黄素(Curcumin),环[Arg-Gly-Asp-D-Phe-Val],环己酰亚胺,环杷明,环磷酰胺,环孢菌素A,环丙孕酮,阿糖胞苷,D12-***素J2,达布拉非尼(Dabrafenib),达卡巴嗪,更生霉素,达沙替尼,道诺霉素,地加瑞克(Degarelix),地诺单抗(Denosumab),***,多西他赛,多柔比星(Doxorubicin),依布硒啉(Ebselen),玫瑰树碱(Ellipticine),恩杂鲁胺(Enzalutamide),表柔比星,厄洛替尼,依托泊苷,依维莫司,依西美坦,氟达拉滨,氟尿嘧啶,氟他胺,亚叶酸,氟维司群(fulvestrant),吉非替尼,格尔德霉素,吉西他滨,染料木黄酮,姜醇,卡莫司汀植入剂(Gliadel Wafer),胶霉毒素,戈瑟瑞林,2-氯-5-硝基苯甲酰苯胺,2-氨基-6-溴-α-氰基-3-(乙氧羰基)-4H-1-苯并吡喃-4-乙酸乙酯,Hinokitiol,羟基脲,索布佐生(Sobuzoxane),伊达比星,异环磷酰胺,伊马替尼,吲哚美辛,伊匹木单抗(Ipilimumab),伊立替康,伊沙匹隆(Ixabepilone),兰瑞肽(Lanreotide),拉帕替尼,来那度胺,来曲唑,甲磺酸乐伐替尼(Lenvatinib),乐卫玛(Lenvima),亚叶酸(Leucovorin),亮丙瑞林(Leuprolide),洛莫司汀,甲孕酮,甲地孕酮,美法仑,Mepesuccinate,巯基嘌呤,Mesna,甲氨蝶呤,甲氧基维拉帕米,苄氧羰基-L-亮氨酰-L-亮氨酰-L-leucinal,丝裂霉素C,米托蒽醌,N,N-二甲基鞘氨醇,奈拉滨(Nelarabine),尼洛替尼(Nilotinib),纳武单抗(Nivolumab),奥曲肽,奥法木单抗(Ofatumumab),寡霉素A,Omacetaxine,奥沙利铂,紫杉醇,帕米膦酸钠(Pamidronate),帕尼单抗(Panitumuma),帕唑帕尼(Pazopanib),培门冬酶(Pegaspargase),培美曲塞,派姆单抗(Pembrolizumab),帕妥珠单抗,Pifithrin,普乐沙福(plerixafor),鬼臼毒素,泊马度胺,波纳替尼(Ponatinib),强的松,2,2-双(羟甲基)-1-氮杂双环[2.2.2]辛-3-酮,丙卡巴嗪,二氯化镭223,雷替曲塞,雷帕霉素,重组人***瘤病毒(HPV)二价疫苗,重组HPV四价疫苗,重组HPV二价,疫苗,重组HPV四价疫苗,重组干扰素α-2b,瑞戈非尼(Regorafenib),白藜芦醇,所有反式视黄酸,Rheumatrex,利妥昔单抗,咯利普兰(Rolipram),Roscovitine,粗糠紫毒素(Rottlerin),紫草素,Sipuleucel-T,西罗莫司,索拉非尼,鞘氨醇,裂殖霉素(Splitomycin),星形孢菌素(Staurosporine),己烯雌酚(Stilboestrol),链脲菌素,3-(4-二甲基氨基苄亚甲基)-2-吲哚二酮,3-[[(4-二甲基-氨基)苯基]亚甲基]-1,3-二氢-2H-吲哚-2-酮,硫化舒林酸,舒尼替尼,他莫昔芬,替莫唑胺,替莫罗莫司(Temsirolimus),沙利度胺,托泊替康,托瑞米芬,曲美替尼,曲妥珠单抗,曲古抑菌素-A,三氟拉嗪,4-[(E)-2-(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)-1-丙烯基]苯甲酸,3,4-二羟基-α-氰基硫代肉桂酰胺,(3-羟基-4-硝基苄亚甲基)丙二腈,凡德他尼(Vandertanib),丙戊酸,维莫非尼(Vemurafenib),维拉帕米,长春碱,长春新碱,长春瑞滨,渥曼青霉素,4-氯-6-(2,3-二甲代苯氨基)-2-嘧啶基硫代乙酸,阿柏西普(Ziv-Aflibercept),唑来膦酸,其盐及其组合。
优选地,一种或多种治疗剂选自但不限于组(A′),即阿比特龙,曲妥珠单抗美坦,阿法替尼,Afinitor(依维莫司),阿那曲唑,阿瓦斯汀,贝伐单抗,卡巴他赛,卡培他滨,卡铂,卡莫司汀,顺铂,克唑替尼,环磷酰胺,地加瑞克,地诺单抗,多西他赛,多柔比星,恩扎鲁胺,表柔比星,厄洛替尼,依托泊苷,依维莫司,依西美坦,氟尿嘧啶,氟维司群,吉非替尼,吉西他滨,伊沙匹隆(Ixabepilone),拉帕替尼,来曲唑,亮丙瑞林(Leuprolide),洛莫司汀,甲地孕酮,甲氨蝶呤,丝裂霉素C,紫杉醇,帕米膦酸,培美曲塞,帕妥珠单抗,强的松,二氯化镭223,Sipuleucel-T,舒尼替尼,他莫昔芬,替莫达(Temodar),替莫唑胺,托泊替康,托瑞米芬,曲妥珠单抗,卡博替尼-S-苹果酸,卡普雷萨(凡德他尼),卡博替尼(卡博替尼-S-苹果酸),盐酸多柔比星,伊匹木单抗,甲磺酸乐伐替尼,Nexavar(甲苯磺酸索拉非尼)纳武单抗,凡德他尼,Yervoy(伊匹木单抗),其盐及其任意组合。
在本发明这方面的一些实施方案中,药物组合物除包含上述式(I)或式(II)的化合物外,还包含一种或多种选自下组的其他治疗剂:
对于急性成淋巴细胞性白血病(ALL):
Abitrexate(甲氨蝶呤),阿霉素PFS(盐酸多柔比星),阿霉素RDF(盐酸多柔比星),Arranon(奈拉滨),天冬酰胺酶菊欧文氏杆菌,Cerubidine(盐酸道诺霉素),Clafen(环磷酰胺),氯法拉滨(Clofarabine),Clofarex(氯法拉滨),Clolar(氯法拉滨),环磷酰胺,阿糖胞苷,Cytosar-U(阿糖胞苷),Cytoxan(环磷酰胺),达沙替尼,盐酸Faunorubicin,盐酸多柔比星,Erwinaze(天冬酰胺酶菊欧文氏杆菌),Folex(甲氨蝶呤),Folex PFS(甲氨蝶呤),格列卫(Gleevec)(甲磺酸伊马替尼),Iclusig(盐酸波纳替尼),甲磺酸伊马替尼,Marqibo(硫酸长春新碱脂质体),巯基嘌呤,甲氨蝶呤,甲氨蝶呤LPF(甲氨蝶呤),Mexate(甲氨蝶呤),Mexate-AQ(甲氨蝶呤),奈拉滨,Neosar(环磷酰胺),Oncaspar(培门冬酶),培门冬酶,Purinethol(巯基嘌呤),红比霉素(盐酸道诺霉素),Sprycel(达沙替尼),Tarabine PFS(阿糖胞苷),Vincasar PFS(硫酸长春新碱),硫酸长春新碱或硫酸长春新碱脂质体;
对于急性髓性白血病(AML):
阿霉素PFS(盐酸多柔比星),阿霉素RDF(盐酸多柔比星),三氧化二砷,Cerubidine(盐酸道诺霉素),Clafen(环磷酰胺),环磷酰胺,阿糖胞苷,Cytosar-U(阿糖胞苷),Cytoxan(环磷酰胺),盐酸道诺霉素,盐酸多柔比星,Neosar(环磷酰胺),红比霉素(盐酸道诺霉素),Tarabine PFS(阿糖胞苷),Trisenox(三氧化二砷),Vincasar PFS(硫酸长春新碱)或硫酸长春新碱;
对于慢性淋巴细胞性白血病(CLL):
阿仑单抗,Ambochlorin(苯丁酸氮芥),Amboclorin(苯丁酸氮芥),Arzerra(奥法木单抗),盐酸苯达莫司汀,Campath(阿仑单抗),苯丁酸氮芥Clafen(环磷酰胺),环磷酰胺,Cytoxan(环磷酰胺),Fludara(氟达拉滨磷酸盐),氟达拉滨磷酸盐,Leukeran(苯丁酸氮芥),Linfolizin(苯丁酸氮芥),Neosar(环磷酰胺),奥法木单抗,Treanda(盐酸苯达莫司汀),苯丁酸氮芥-强的松,或CVP(环磷酰胺、长春新碱和强的松的组合);
对于慢性髓性白血病(CML):
Bosulif(博舒替尼),博舒替尼,Clafen(环磷酰胺),环磷酰胺,阿糖胞苷,Cytosar-U(阿糖胞苷),Cytoxan(环磷酰胺),达沙替尼,格列卫(甲磺酸伊马替尼),Iclusig(盐酸波纳替尼),甲磺酸伊马替尼,Neosar(环磷酰胺),尼洛替尼,高三尖杉酯碱(Omacetaxine Mepesuccinate),盐酸波纳替尼,Sprycel(达沙替尼),Synribo(高三尖杉酯碱),Tarabine PFS(阿糖胞苷)或Tasigna(尼洛替尼);
对于脑膜白血病:
阿糖胞苷,Cytosar-U(阿糖胞苷)或Tarabine PFS(阿糖胞苷);
对于伯基特氏淋巴瘤:
甲氨蝶呤(抗风湿性)口服,美罗华iv,甲氨蝶呤钠口服,***口服,DexPak,利妥昔单抗iv,甲氨蝶呤钠注射剂,阿霉素iv,环磷酰胺口服,Trexall口服,长春新碱iv,环磷酰胺iv,***磷酸钠注射剂,***Intensol口服,甲氨蝶呤钠(PF)注射剂,Rheumatrex口服,阿糖胞苷注射剂,多柔比星iv,***磷酸钠(PF)注射剂,依托泊苷iv,异环磷酰胺iv,Ifex iv,阿糖胞苷(PF)注射剂,阿霉素PFS iv,DexPak 10天口服,DexPak 6天口服,异环磷酰胺美司钠iv,Toposar iv,磷酸依托泊苷iv,Etopophos iv,Vincasar PFSiv或Baycadron口服;
对于弥漫性大细胞淋巴瘤:
强的松口服,美罗华iv,***口服,DexPak 13天口服,利妥昔单抗iv,阿霉素iv,环磷酰胺口服,强的松Intensol口服,长春新碱iv,环磷酰胺iv,博来霉素注射,***磷酸钠注射,***Intensol口服,阿糖胞苷注射,美法仑口服,多柔比星iv,Alkeran口服,依托泊苷口服,***磷酸钠(PF)注射,美法仑iv,丙卡巴嗪口服,依托泊苷iv,阿糖胞苷(PF)注射,阿霉素PFS iv,DexPak 10天口服,DexPak 6天口服,Rayos口服,Alkeraniv,Matulane口服,表柔比星iv,Toposar iv,依托泊苷磷酸盐iv,Etopophos iv,Ellenceiv,Vincasar PFS iv或Baycadron口服;
对于脑癌:
Afinitor(依维莫司),阿瓦斯汀(贝伐单抗),BiCNU(卡莫司汀),卡莫司汀片(CArmustine wafer),洛莫司汀,替莫达(替莫唑胺),替莫唑胺,替莫达口服,长春新碱iv,Camptosar iv,伊立替康iv,贝伐单抗iv,替莫唑胺口服,Gliadel Wafer植入,丙卡巴嗪口服,BiCNU iv,替莫达iv,Matulane口服,Vincasar PFS iv,卡莫司汀iv,聚苯丙生中的卡莫司汀植入剂,或替莫唑胺iv;
对于多发性骨髓瘤和其他浆细胞赘生物:
Aredia(帕米膦酸二钠),硼替佐米,卡非佐米,Clafen(环磷酰胺),环磷酰胺,Cytoxan(环磷酰胺),Doxil(盐酸多柔比星脂质体),盐酸多柔比星脂质体,Dox-SL(盐酸多柔比星脂质体),Evacet(盐酸多柔比星脂质体),Kyprolis(卡非佐米),来那度胺,LipoDox(盐酸多柔比星脂质体),Mozobil(普乐沙福),Neosar(环磷酰胺),帕米膦酸二钠,普乐沙福,Pomalidomide(泊马度胺(Pomalyst)),泊马度胺,Revlimid(来那度胺),Synovir(沙利度胺(Thalidomide)),沙利度胺,Thalomid(沙利度胺),Velcade(硼替佐米),唑来膦酸,或Zometa(唑来膦酸);对于非小细胞肺癌:
Abitrexate(甲氨蝶呤),Abraxane(紫杉醇白蛋白稳定化的纳米颗粒制剂),阿法替尼(Afatinib)马来酸氢盐,Alimta(培美曲塞二钠),阿瓦斯汀(贝伐单抗),贝伐单抗,卡铂,顺铂,克唑替尼,盐酸厄洛替尼,Folex(甲氨蝶呤),Folex PFS(甲氨蝶呤),吉非替尼,Gilotrif(阿法替尼马来酸氢盐),吉西他滨盐酸盐,Gemzar(吉西他滨盐酸盐),易瑞沙(Iressa)(吉非替尼),甲氨蝶呤,甲氨蝶呤LPF(甲氨蝶呤),Mexate(甲氨蝶呤),Mexate-AQ(甲氨蝶呤),紫杉醇,紫杉醇白蛋白稳定化的纳米颗粒制剂,Paraplat(卡铂),Paraplatin(卡铂),培美曲塞二钠,Platinol(顺铂),Platinol-AQ(顺铂),特罗凯(Tarceva)(盐酸厄洛替尼),泰素(Taxol)(紫杉醇),Xalkori(克唑替尼),卡铂-泰素的组合,或吉西他滨-顺铂的组合;
对于小细胞肺癌:
Abitrexate(甲氨蝶呤),Etopophos(依托泊苷磷酸盐),依托泊苷,依托泊苷5磷酸盐,Folex(甲氨蝶呤),Folex PFS(甲氨蝶呤),Hycamtin(盐酸托泊替康),甲氨蝶呤,甲氨蝶呤LPF(甲氨蝶呤),Mexate(甲氨蝶呤),Mexate-AQ(甲氨蝶呤),Toposar(依托泊苷),盐酸托泊替康,或VePesid(依托泊苷);
对于膀胱癌:
阿霉素PFS(盐酸多柔比星),阿霉素RDF(盐酸多柔比星),顺铂,盐酸多柔比星,Platinol(顺铂)或Platinol-AQ(顺铂);
对于乳腺癌:
Perjeta(帕妥珠单抗),Abitrexate(甲氨蝶呤),Abraxane(紫杉醇白蛋白稳定化的纳米颗粒制剂),曲妥珠单抗美坦,阿霉素PFS(盐酸多柔比星),阿霉素RDF(盐酸多柔比星),Adrucil(氟尿嘧啶),Afinitor(依维莫司),阿那曲唑,Aredia(帕米膦酸二钠),Arimidex(阿那曲唑),Aromasin(依西美坦),卡培他滨,Clafen(环磷酰胺),环磷酰胺,Cytoxan(环磷酰胺),多西他赛,盐酸多柔比星,Efudex(氟尿嘧啶),Ellence(盐酸表柔比星),盐酸表柔比星,依维莫司,依西美坦,Fareston(托瑞米芬(Toremifene)),Faslodex(氟维司群),Femara(来曲唑),Fluoroplex(氟尿嘧啶),氟尿嘧啶,Folex(甲氨蝶呤),FolexPFS(甲氨蝶呤),氟维司群,盐酸吉西他滨,Gemzar(盐酸吉西他滨),赫塞汀(Herceptin)(曲妥珠单抗),伊沙匹隆,
Ixempra(伊沙匹隆),Kadcyla(曲妥珠单抗美坦),二甲苯磺酸拉帕替尼,来曲唑,Megace(醋酸甲地孕酮),醋酸甲地孕酮,甲氨蝶呤,甲氨蝶呤LPF(甲氨蝶呤),Mexate(甲氨蝶呤),Mexate-AQ(甲氨蝶呤),Neosar(环磷酰胺),Nolvadex(他莫昔芬柠檬酸盐),Novaldex(他莫昔芬柠檬酸盐),紫杉醇,紫杉醇白蛋白稳定化的纳米颗粒制剂,帕米膦酸二钠,Perjeta(帕妥珠单抗),帕妥珠单抗,他莫昔芬柠檬酸盐,泰素(紫杉醇),Taxotere(多西他赛),曲妥珠单抗,托瑞米芬,Tykerb(拉帕替尼二甲苯磺酸盐)或希罗达(Xeloda)(卡培他滨);
对于***:
Blenoxane(博来霉素),博来霉素,顺铂,Hycamtin(盐酸托泊替康),Platinol(顺铂),Platinol-AQ(顺铂),盐酸托泊替康,或吉西他滨-顺铂的组合;
对于子宫内膜癌:
紫杉醇,多西他赛,多柔比星,顺铂,卡铂,卡培他滨,吉西他滨,他莫昔芬,己酸羟孕酮,来曲唑,醋酸甲地孕酮(megestrol),甲孕酮(medroxyprogesterone);对于食道癌:
Cyramza(雷莫芦单抗(Ramucirumab)),多西他赛,赫塞汀(曲妥珠单抗),雷莫芦单抗,曲妥珠单抗;
对于结肠癌:
Adrucil(氟尿嘧啶),阿瓦斯汀(贝伐单抗),贝伐单抗,Camptosar(盐酸伊立替康),卡培他滨,西妥昔单抗,Efudex(氟尿嘧啶),Eloxatin,奥沙利铂),爱必妥(Erbitux)(西妥昔单抗),Fluoroplex(氟尿嘧啶),氟尿嘧啶,盐酸伊立替康,亚叶酸钙,奥沙利铂,帕尼单抗,瑞戈非尼,Stivarga(瑞戈非尼),Vectibix(帕尼单抗),Wellcovorin(亚叶酸钙),希罗达(卡培他滨),Zaltrap(阿柏西普(Ziv-Aflibercept)),阿柏西普,CAPOX(卡培他滨和奥沙利铂的组合),FOLFIRI(亚叶酸,氟尿嘧啶和伊立替康的组合),FOLFIRI-贝伐单抗(亚叶酸,氟尿嘧啶,伊立替康和贝伐单抗的组合),FOLFIRICetuximab(亚叶酸,氟尿嘧啶,伊立替康和西妥昔单抗的组合),FOLFOX(亚叶酸,氟尿嘧啶和奥沙利铂的组合)或XELOX(卡培他滨和奥沙利铂的组合);
对于直肠癌:
Adrucil(氟尿嘧啶),阿瓦斯汀(贝伐单抗),贝伐单抗,Camptosar(盐酸伊立替康),西妥昔单抗,Efudex(氟尿嘧啶),爱必妥(西妥昔单抗),Fluoroplex(氟尿嘧啶),氟尿嘧啶,盐酸伊立替康,帕尼单抗,瑞戈非尼,Stivarga(瑞戈非尼),Vectibix(帕尼单抗),Zaltrap(阿柏西普),阿柏西普,CAPOX,FOLFIRI,FOLFIRI-贝伐单抗,FOLFIRI-西妥昔单抗,FOLFOX或XELOX;
对于胃癌:
阿霉素PFS(盐酸多柔比星),阿霉素RDF(盐酸多柔比星),Adrucil(氟尿嘧啶),多西他赛,盐酸多柔比星,Efudex(氟尿嘧啶),Fluoroplex(氟尿嘧啶),氟尿嘧啶,赫塞汀(曲妥珠单抗),丝裂霉素C,Mitozytrex(丝裂霉素C),突变霉素(丝裂霉素C),Taxotere(多西他赛)或曲妥珠单抗;
对于胶质母细胞瘤:
Avastin(贝伐单抗),替莫达口服,长春新碱iv,Camptosar iv,伊立替康iv,贝伐单抗iv,替莫唑胺口服,Gliadel Wafer植入,丙卡巴嗪口服,BiCNU iv,替莫达iv,Matulane口服,Vincasar PFS iv,卡莫司汀iv,聚苯丙生中的卡莫司汀植入剂或替莫唑胺iv;
对于肝细胞癌:
索拉非尼,舒尼替尼,厄洛替尼,贝伐单抗或西罗莫司;
对于大细胞神经内分泌癌:
舒尼替尼(Sutent),依维莫司(Afinitor),或氟尿嘧啶(Adrucil,5-FU)、多柔比星(阿霉素)和链脲霉素(Zanosar)的组合;
对于黑色素瘤:
阿地白介素,达布拉非尼,达卡巴嗪,DTIC-Dome(达卡巴嗪),内含子A(重组干扰素α-2b),伊匹木单抗,Mekinist(曲美替尼),聚乙二醇化干扰素α-2b,PEG-Intron(聚乙二醇化干扰素α-2b),Proleukin(阿地白介素),重组干扰素α-2b,Sylatron(聚乙二醇化干扰素α-2b),Tafinlar(达布拉非尼),曲美替尼,维莫非尼,Yervoy(伊匹木单抗)或Zelboraf(维莫非尼);
对于神经母细胞瘤:
阿霉素PFS(盐酸多柔比星),阿霉素RDF(盐酸多柔比星),Clafen(环磷酰胺),环磷酰胺,Cytoxan(环磷酰胺),盐酸多柔比星,Neosar(环磷酰胺),Vincasar PFS(硫酸长春新碱)或长春新碱硫酸盐;
对于卵巢癌:
阿霉素PFS(盐酸多柔比星),阿霉素RDF(盐酸多柔比星),卡铂,Clafen(环磷酰胺),顺铂,环磷酰胺,Cytoxan(环磷酰胺),盐酸多柔比星,Dox-SL(盐酸多柔比星脂质体),DOXIL(盐酸多柔比星脂质体),盐酸多柔比星脂质体,Evacet(盐酸多柔比星脂质体),吉西他滨盐酸盐,Gemzar(盐酸吉西他滨),Hycamtin(盐酸托泊替康),LipoDox(盐酸多柔比星脂质体),Neosar(环磷酰胺),紫杉醇,Paraplat(卡铂),Paraplatin(卡铂),Platinol(顺铂),Platinol-AQ(顺铂),泰素(紫杉醇),盐酸托泊替康,BEP(博来霉素,依托泊苷和顺铂的组合),或卡铂-泰素的组合,或吉西他滨-顺铂的组合;
对于头颈癌:
博来霉素,西妥昔单抗,多西他赛,爱必妥(西妥昔单抗),Hydrea(羟脲),Keytruda(派姆单抗),甲氨蝶呤,纳武单抗,Taxotere(多西他赛)Trexall(甲氨蝶呤);
对于肝癌:
Nexavar(甲苯磺酸索拉非尼),瑞戈非尼,甲苯磺酸索拉非尼,Stivarga(瑞戈非尼);
对于甲状腺癌:
卡博替尼-S-苹果酸盐,Caprelsa(凡德他尼),Cometriq(卡博替尼-S-苹果酸盐),盐酸多柔比星,伊匹木单抗,甲磺酸乐伐替尼,Lenvima(甲磺酸乐伐替尼),Nexavar(甲苯磺酸索拉非尼),纳武单抗,凡德他尼,Yervoy(伊匹木单抗);
对于胰腺癌:
Abraxane,Nab-紫杉醇,舒尼替尼,依维莫司,Adrucil(氟尿嘧啶),Efudex(氟尿嘧啶),盐酸厄洛替尼,Fluoroplex(氟尿嘧啶),氟尿嘧啶,吉西他滨盐酸盐,Gemzar(吉西他滨盐酸盐),丝裂霉素C,Mitozytrex(丝裂霉素C),突变霉素(丝裂霉素C),或特罗凯(盐酸厄洛替尼);
对于***癌:
Blenoxane(博来霉素)或博来霉素;
对于***癌:
醋酸阿比特龙,卡巴他赛,地加瑞克,地诺单抗,多西他赛,恩杂鲁胺,Jevtana(卡巴他赛),醋酸亮丙瑞林,Lupron(醋酸亮丙瑞林),Lupron Depot(醋酸亮丙瑞林),LupronDepot-3个月(醋酸亮丙瑞林),Lupron Depot-4个月(醋酸亮丙瑞林),Lupron Depot-Ped(醋酸亮丙瑞林),强的松,Prolia(地诺单抗),Provenge(Sipuleucel-T),二氯化镭223,Sipuleucel-T,Taxotere(多西他赛),Viadur(醋酸亮丙瑞林),Xgeva(地诺单抗),Xofigo(二氯化镭223),Xtandi(恩杂鲁胺)或Zytiga(醋酸阿比特龙);
对于肾透明细胞癌:
Afinitor(依维莫司),阿地白介素,阿瓦斯汀(贝伐单抗),阿昔替尼,贝伐单抗,依维莫司,Inlyta(阿昔替尼),Nexavar(甲苯磺酸索拉非尼),盐酸帕唑帕尼,Proleukin(阿地白介素),甲苯磺酸索拉非尼,苹果酸舒尼替尼,Sutent(苹果酸舒尼替尼),替莫罗莫司,Torisel(替莫罗莫司)或Votrient(盐酸帕唑帕尼);
对于视网膜母细胞瘤:
Clafen(环磷酰胺),环磷酰胺,Cytoxan(环磷酰胺)或Neosar(环磷酰胺);对于横纹肌肉瘤:Cosmegen(更生霉素),更生霉素,Vincasar PFS(长春新碱硫酸盐)或长春新碱硫酸盐,和
对于***的预防:
Cervarix(重组人***瘤病毒(HPV)二价疫苗),Gardasil(重组HPV四价疫苗),重组HPV二价重组疫苗,重组HPV四价疫苗。
在本发明该方面的一些实施方案中,药物组合物包含式(I)的化合物,或优选地具有式(II)的化合物,以及备选地或除了如上所述的组(A)或(A')的其他治疗剂之外,包含一种或多种选自下组(B)的其他治疗剂:
乙酰水杨酸,二氟尼柳(Diflunisal),水杨酰水杨酸,布洛芬,右布洛芬,萘普生,非诺洛芬(Fenoprofen),酮洛芬(Ketoprofen),右旋酮洛芬(Dexketoprofen),氟比洛芬(Flurbiprofen),奥沙普嗪(Oxaprozin),洛索洛芬(Loxoprofen),吲哚美辛(Indomethacin),托美汀(Tolmetin),舒林达克(Sulindac),依托度酸(Etodolac),酮咯酸(Ketorolac),双氯芬酸(Diclofenac),萘丁美酮(Nabumetone),吡罗昔康(Piroxicam),美洛昔康(Meloxicam),替诺昔康(Tenoxicam),屈昔康(Droxicam),氯诺昔康(Lornoxicam),伊索昔康(Isoxicam),甲芬那酸(Mefenamic acid),甲氯芬那酸(Meclofenamic acid),氟芬那酸(Flufenamic acid),托芬那酸(Tolfenamic acid),塞来昔布(Celecoxib),罗非考昔(Rofecoxib),Valdecosib,帕瑞昔布(Parecoxib),鲁米昔布(Lumiracoxib),依托昔布(Etoricoxib),非罗考昔(Firocoxib),尼美舒利(Nimesulide),利克飞龙(Licofelone),H-哈巴苷(H-harpagide),赖氨酸氯尼辛,其盐,及其组合。优选地,该方面中的一种或多种其他治疗剂是选择性环加氧酶-2(COX-2)抑制剂。因此,在一些优选的实施方案中,其他治疗剂选自由以下组成的组(B'):
塞来昔布(Celecoxib),罗非考昔(Rofecoxib),Valdecosib,帕瑞昔布(Parecoxib),鲁米昔布(Lumiracoxib),依托昔布(Etoricoxib),非罗考昔(Firocoxib),其药学上可接受的盐,及其组合。
药物制剂
本发明的另一方面涉及药物制剂,其包含式(I)或优选地式(II)或式(III)或式(IV)的化合物,或如上所述的药物组合物(其可以另外包含上述的其他治疗剂、形成三螺旋的寡核苷酸(TFO)和/或抗代谢物),以及至少一种药学上可接受的载体。
所述至少一种药学上可接受的载体选自下组:花生油,芝麻油,棉籽油,玉米油,橄榄油和油的混合物;油酸乙酯,肉豆蔻酸异丙酯,脂肪酸甘油酯,乙酰化脂肪酸甘油酯;乙醇,异丙醇,十六烷醇,甘油和丙二醇,聚乙二醇,矿物油,矿脂;水,无菌水,林格氏溶液,等渗盐水溶液,右旋糖溶液,葡萄糖溶液;β-环糊精,羟丙基-β-环糊精;微晶纤维素,结晶纤维素,羟丙基纤维素,羟丙基甲基纤维素,甲基纤维素,羧甲基纤维素,羧甲基纤维素钠,羧甲基纤维素钙,邻苯二甲酸醋酸纤维素,醋酸丁酸纤维素,羟乙基纤维素,乙基纤维素;及其组合。
在优选的实施方案中,药学上可接受的载体选自下组:β-环糊精,羟丙基-β-环糊精,羟丙基纤维素,羟丙基甲基纤维素,甲基纤维素,羧甲基纤维素,羟乙基纤维素,乙基纤维素及其组合。在某些优选的实施方案中,药学上可接受的载体选自羟丙基-β-环糊精,羧甲基纤维素及其组合。
上文提述的化合物(优选具有式(II)的化合物)或包含上述任何化合物的化合物(优选具有式(II)的化合物)的药物制剂,包含至少一种如上所述的药学上可接受的载体,从而所述制剂通常为胶囊剂,扁囊剂,片剂,锭剂,粉剂,颗粒剂,口服混悬剂或溶液的形式。
涉及式(I)化合物的治疗方法
本发明的另一方面涉及在哺乳动物中治疗或预防癌性疾病的方法,该方法包括对需要这种治疗的哺乳动物施用治疗有效量的本发明的化合物,本发明的药物组合物或本发明的药物制剂。
本发明的式(I)化合物,药物组合物或药物制剂优选通过选自以下的途径施用:口服,含服,舌下,经皮,经粘膜,鼻内,静脉内,腹膜内,肌内,皮下和鞘内施用,优选通过口服、含服或舌下途径施用。
在本发明该方面的其他实施方案中,另外的治疗剂选自如上所述的组(B)。优选地,另外的治疗剂是选择性COX-2抑制剂之一或选自如上所述的组(B’)。
如上所述的治疗方法还可包括选自放射疗法、手术或其组合的另外的治疗。所述另外的治疗可以在本文所述的式(I)的化合物、药物组合物或药物制剂的施用之前或之后进行。
在本发明的上述方面中要治疗或预防的癌性疾病优选地易感于PI3Kα突变和/或过度活化,和/或扩增和/或失调。癌性疾病也可以由这种PI3Kα突变的存在诱发或触发。
优选地,在本发明的上述方面中要治疗或预防的癌性疾病选自由以下组成的组(C):
急性单核细胞白血病,急性髓性白血病,急性骨髓单核细胞白血病,急性早幼粒细胞白血病,成人T细胞白血病,成人T细胞淋巴瘤,星形细胞瘤,非典型类癌肺癌,基底细胞癌,B急性淋巴细胞白血病,B细胞急性成淋巴细胞性白血病/淋巴瘤,膀胱癌,脑癌,乳腺癌,支气管癌,伯基特氏淋巴瘤,胆管癌,原发性来源未知的癌,***,慢性骨髓增生性病症,结肠癌,弥漫性大细胞淋巴瘤,子宫内膜癌,室管膜瘤,食道癌,胃癌,胶质瘤,胶质母细胞瘤,头颈癌,血管外皮细胞瘤,肝细胞癌,霍奇金氏淋巴瘤,卡波济肉瘤,肾癌,大细胞神经内分泌癌,大颗粒性淋巴细胞白血病,白血病,肝癌,肺癌,淋巴瘤,髓母细胞瘤,黑色素瘤,多发性骨髓瘤,骨髓增生异常综合征,鼻咽癌,神经母细胞瘤,NK细胞瘤,非霍奇金氏淋巴瘤,食道鳞状细胞癌,骨肉瘤,卵巢癌,胰腺癌,外周T细胞白血病,原发性浆细胞白血病,***癌,肾透明细胞癌,视网膜母细胞瘤,横纹肌肉瘤,肉瘤,小细胞肺癌,T细胞急性成淋巴细胞性白血病,T细胞急性成淋巴细胞性淋巴瘤,睾丸癌,胸腺瘤,甲状腺癌,脐尿管癌,子宫癌,***癌及其组合。
更优选地,该癌性疾病选自下组(C’):B急性淋巴细胞白血病,伯基特氏淋巴瘤,弥漫性大细胞淋巴瘤,多发性骨髓瘤,原发性浆细胞白血病,非典型类癌肺癌,膀胱癌,脑癌,乳腺癌,***,结肠癌,子宫内膜癌,胃癌,胶质母细胞瘤,头颈癌,肝细胞癌,大细胞神经内分泌癌,肝癌,髓母细胞瘤,黑素瘤,神经母细胞瘤,食道鳞状细胞癌,骨肉瘤,卵巢癌,垂体癌,***癌,肾透明细胞癌,视网膜母细胞瘤,横纹肌肉瘤,小细胞肺癌及其组合。
已经发现本文所述的式(I)的化合物,药物组合物或药物制剂特别适用于治疗或预防选自下组的癌性疾病:胰腺癌,乳腺癌,***癌和肺癌,优选地尤其是胰腺癌或乳腺癌,结肠癌,子宫内膜癌,脑瘤,皮肤癌,卵巢癌,胃癌,肺癌,甲状腺癌,头颈癌,***,肝/胆道癌,垂体瘤,白血病/淋巴瘤,神经母细胞瘤。
在本发明上述方面的某些实施方案中,癌性疾病是腺癌。优选地,在这些实施方案中,癌性疾病选自下组:
结肠腺癌,肺腺癌,***腺癌,脐尿管腺癌,***腺癌,乳腺腺癌,食道腺癌,支气管腺癌,胰腺腺癌,子宫内膜腺癌,卵巢腺癌,胃腺癌,肝腺癌,甲状腺腺癌,头颈腺癌,膀胱腺癌和胃肠道腺癌。
更优选地,要治疗或预防的癌性疾病是胰腺导管腺癌,乳腺腺癌,***腺癌,子宫内膜腺癌,卵巢腺癌,胃腺癌,肝腺癌,甲状腺腺癌,头和颈腺癌,膀胱腺癌,和胃肠道腺癌或肺腺癌,最优选选自胰腺导管腺癌,乳腺腺癌,子宫内膜腺癌,卵巢腺癌,胃腺癌,肝腺癌,甲状腺腺癌,头和颈腺癌,膀胱腺癌和胃肠道腺癌,以及肺腺癌。
用于医药的化合物和药物组合物
本发明的另一方面涉及式(I)或优选地式(II)或(III)或(IV)的化合物,药物组合物(任选地包含一种或多种另外的治疗剂和/或抗代谢物),或包含上述的化合物或药物组合物的药物制剂,其用于医药。
在一些实施方案中,所述化合物、组合物和制剂优选用于治疗或预防哺乳动物的癌性疾病。哺乳动物优选是人类。所述癌性疾病尤其是易感于PI3Kα突变、由其引起或触发(如上文所述)的癌症。因此,要通过施用本发明的化合物、组合物或制剂来治疗的优选的受试者表现出PI3Kα突变,其易感于式(I)化合物的变构抑制作用。更优选地,要治疗的受试者在编码PI3Kα的基因中携带突变,该突变导致如上所述的PI3Kα突变体特别是H1047R突变体的出现。通过施用本发明的化合物、组合物或制剂来治疗受试者以预防癌性疾病的发作或治疗已经存在的癌性疾病。
在优选的实施方案中,用于以上提及的医药用途的所述化合物、组合物和制剂包含治疗有效量的以上提及的式(I)的化合物,以施用于需要其的受试者。
本文所述的任何式(I)化合物,优选地式(II)或(III)或(IV)化合物,本发明的药物组合物或药物制剂,均优选包含具有式(II)或(III)或(IV)的化合物,优选通过选自口服,含服,舌下,经皮,经粘膜,鼻内,静脉内,腹膜内,肌内,皮下和鞘内施用的途径施用,优选通过口服、含服或舌下施用途径。
在本发明该方面的其他实施方案中,一种或多种其他治疗剂另外地或备选地选自如上文在化合物和药物组合物部分中所述的组(B)。优选地,其他治疗剂是选自如上所述的组(B’)的选择性COX-2抑制剂中的一种。
在一些实施方案中,化合物、药物组合物或包含上述化合物或药物组合物的制剂用于治疗易感于PI3Kα突变和/或过度活化、和/或扩增、和/或失调的癌性疾病的方法中。
优选地,在本发明的上述实施方案中要治疗或预防的癌性疾病选自下组(C):
急性单核细胞白血病,急性髓性白血病,急性骨髓单核细胞白血病,急性早幼粒细胞白血病,成人T细胞白血病,成人T细胞淋巴瘤,星形细胞瘤,非典型类癌肺癌,基底细胞癌,B急性淋巴细胞白血病,B细胞急性成淋巴细胞性白血病/淋巴瘤,膀胱癌,脑癌,乳腺癌,支气管癌,伯基特氏淋巴瘤,胆管癌,原发性来源未知的癌,***,慢性骨髓增生性病症,结肠癌,弥漫性大细胞淋巴瘤,子宫内膜癌,室管膜瘤,食道癌,胃癌,胶质瘤,胶质母细胞瘤,头颈癌,血管外皮细胞瘤,肝细胞癌,霍奇金氏淋巴瘤,卡波济肉瘤,肾癌,大细胞神经内分泌癌,大颗粒性淋巴细胞白血病,白血病,肝癌,肺癌,淋巴瘤,髓母细胞瘤,黑素瘤,多发性骨髓瘤,骨髓增生异常综合征,鼻咽癌,神经母细胞瘤,NK细胞瘤,非霍奇金氏淋巴瘤,食道鳞状细胞癌,骨肉瘤,卵巢癌,胰腺癌,外周T细胞白血病,原发性浆细胞白血病,***癌,肾透明细胞癌,视网膜母细胞瘤,横纹肌肉瘤,肉瘤,小细胞肺癌,皮肤癌,T细胞急性成淋巴细胞白血病,T细胞急性成淋巴细胞淋巴瘤,睾丸癌,胸腺瘤,甲状腺癌,脐尿管癌,子宫癌,***癌及其组合。
更优选地,所述癌性疾病选自下组(C’):B急性淋巴细胞白血病,伯基特氏淋巴瘤,弥漫性大细胞淋巴瘤,多发性骨髓瘤,原发性浆细胞白血病,非典型类癌肺癌,膀胱癌,脑癌,乳腺癌,***,结肠癌,胃癌,胶质母细胞瘤,肝细胞癌,大细胞神经内分泌癌,肝癌,子宫内膜癌,髓母细胞瘤,黑素瘤,神经母细胞瘤,食道鳞状细胞癌,骨肉瘤,卵巢癌,子宫内膜癌,***癌,皮肤癌,肾透明细胞癌,视网膜母细胞瘤,横纹肌肉瘤,小细胞肺癌,甲状腺癌及其组合。
已经发现化合物,优选式(II)或(III)或(IV)的化合物,如本文中上述的药物组合物或包含所述化合物或药物组合物的药物制剂特别适合用于治疗选自下组的癌性疾病:乳腺癌,子宫内膜癌,结肠癌,脑癌,皮肤癌,卵巢癌,胃癌,肺癌,甲状腺癌,头颈癌,***,胰腺癌,肝/胆道癌,垂体瘤,泌尿道肿瘤,白血病/淋巴瘤,神经母细胞瘤,优选特别是结肠癌,脑癌,子宫内膜癌或乳腺癌。
在本发明上述方面的一些实施方案中,癌性疾病是腺癌。优选地,癌性疾病在这些实施方案中选自下组:胰腺导管腺癌,乳腺腺癌,***腺癌,子宫内膜腺癌,卵巢腺癌,胃腺癌,肝腺癌,甲状腺腺癌,头颈腺癌,膀胱腺癌,和胃肠道腺癌或肺腺癌,最优选选自胰腺导管腺癌,乳腺腺癌,子宫内膜腺癌,卵巢腺癌,胃腺癌,肝腺癌,甲状腺腺癌,头颈腺癌,膀胱腺癌,和胃肠道腺癌以及肺腺癌。
制备式(I)化合物的方法
本发明的另一方面涉及用于制备本文所述的任何式(I)的化合物的方法。通常,式(I)化合物是通过将具有式(V)的二氯类似物烷基化制备的
其中L独立地为H或OH;X独立地为N或C;Y独立地为H或=O,
其通过与式R1-Z-H的化合物反应,其中Z独立地为S或NH,并且R1独立地为单环或多环芳基、杂芳基或环烷基,包括但不限于以下实例:
其中R2独立地是羟基,氢,氟,氯或溴中的至少一种;Y1独立地为C,O,S,NH或N,其中Y1为O,S和NH的定义优选应用于五元芳族环系,而Y1为N的定义优选应用于六元环,得到相应的式(I)的取代的苄基或吡啶。任选地,随后将式(I)的化合物转化为相应的药学上可接受的盐形式。
在一个优选的实施方案中,该方法涉及制备式(II)的化合物或其药学上可接受的盐形式,其通过使式R1-Z-H的化合物(其中R1和Z如上定义)与式(V)的二氯化物反应
其中R1,L,Z,X如上所定义,且Y=H,以得到式(II)的化合物,并任选地将其转化为其相应的盐形式。
在其他优选的实施方案中,该方法涉及制备式(III)或(IV)的化合物或其药学上可接受的盐形式,其通过使式R1-Z-H的化合物(其中R1和Z如上定义)与式(V)的二氯化物反应
其中R1,L,Z,X如上定义,且Y为=O,以得到式(III)或(IV)的化合物,并任选地将其转化为其相应的盐形式。
相应的式(V)的氯化物可以商购获得或可以通过以下实例流程合成
优选地,式(I)的化合物,尤其是式(II)的化合物可以根据实施例1中所述的路线合成(关于反应条件、溶剂等的详细信息,参见实施例1)。本发明的一个特别优选的实施方案是将产物从H2O和MeOH中结晶,导致产物的高产率和/或纯度。在此方面,对于本领域技术人员而言,如何通过与各自的中间体进行相似的反应步骤以类似于实施例1所示的反应方案来合成除式(II)的化合物以外的式(I)的化合物将是明显的。
优选地,式(I)的化合物,特别是式(III)的化合物可以根据实施例2中所述的路线合成(关于反应条件、溶剂等的详细信息,参见实施例2)。在此方面,对于本领域技术人员而言,如何通过与各自的中间体进行相似的反应步骤以类似于实施例2所示的反应方案来合成除式(III)的化合物以外的式(I)的化合物将是明显的。
优选地,式(I)的化合物,尤其是式(IV)的化合物可以根据实施例3中所述的路线合成(关于反应条件、溶剂等的细节参见实施例3)。在此方面,对于本领域技术人员而言,如何通过与各自的中间体进行相似的反应步骤以类似于实施例3所示的反应方案来合成除式(IV)的化合物以外的式(I)的化合物将是明显的。
用于测定PI3Kα或PI3Kα突变体活性的测定法
本发明的另一个方面是本说明书前面已经提到的磷脂酰肌醇3-激酶α的新活性测定法。迄今为止描述的测定法是费时的或者需要专门的设备。此处描述的测定法快速且使用常规设备。通过如实地概括膜结合酶的特性,该测定法定量评估了PI3Kα的活性。
该测定法包括
a)固相,在固相处GST-GRP1分子变为固定化的,
b)将PI3Kα或PI3Kα突变体与缓冲液、ATP和PIP2孵育,以催化PIP2向PIP3的转化,
c)添加具有可检测标记或报告分子的竞争者PIP3,以及
d)确定酶活性,其基于在步骤b)中获得的与竞争者PIP3竞争结合功能化固相的PIP3的量。
这种新的测定法基于PI3K催化的反应产物PIP3与具有pleckstrin同源性(PH)结构域的蛋白(例如,磷酸肌醇同等型1的通用受体(GRP1PH))结合的高亲和力和特异性,而PI3Kα催化反应的底物PIP2仅最少地与GRP1结合(Lindsay等人,J Cell Sci.119:5160-5168(2006),Ferguson等人,Mol Cell 6:373-84(2000),Fleming等人,Biochem J 351:173-182(2000))。因此,该发明性的活性测定法通过以间接竞争性测试形式确定酶促产生的PIP3的量来测量PI3Kα或PI3Kα突变体的活性。此外,(潜在的)抑制剂分子对PI3Kα或PI3Kα突变体的活性的影响可以通过该发明性的测定法来确定。
优选地,通过提供功能化的固相(优选地为孔板)来进行测试,在固相上固定GRP1分子,优选地为结合至谷胱甘肽包被的固相的GST(谷胱甘肽-S转移酶)-GRP1复合物。为此,可以通过在适当的表达***中表达编码融合蛋白GST-GRP1的cDNA来生产GST-GRP1。这样的表达***优选地是用于重组蛋白表达的细菌表达***,优选地是基于大肠杆菌的表达***,特别是其中在***合适的表达载体后cDNA转化的大肠杆菌的BL21(DE3)菌株。表达的蛋白质可以例如通过亲和层析纯化,优选使用谷胱甘肽-琼脂糖4B层析材料。
该测定法包括添加PIP3竞争者分子,其优选携带可检测的标记物或报告分子,在进一步反应时能够检测竞争者PIP3的存在。在一个特别优选的实施方案中,竞争者PIP3是生物素-PIP3,并且在进一步反应中,将存在于生物素结合伴侣链霉亲和素上的标记物用于检测。特别优选的标记物是辣根过氧化物酶(HRP),当其与适当的底物接触时提供易于检测的颜色或荧光信号。定量可以通过以下进行,添加带有可检测的标记物的生物素结合伴侣例如链霉亲和素-HRP缀合物,然后与产生可检测产物的HRP的底物例如OBD一起温育,其被转化为在492nm处测量吸光度时吸收光的产物。对捕获的竞争者PIP3的量的定量可以直接进行,也可以在测试过程的更后期阶段进行。
在实施测定法的一个优选方式中,将竞争者PIP3直接加入到功能化的固相并与固相上的GST-GRP1复合物形成稳定的复合物,然后在去除过量的反应物后对捕获的竞争者PIP3进行定量。
在本发明的另一个优选的实施方案中,将竞争者PIP3添加到固相中,这是与PI3Kα或PI3Kα突变体催化反应的PIP3产物一起添加的或在其添加之后进行的。由于PIP3和竞争者PIP3与固相的竞争性结合以及通过竞争者PIP3随附的可检测标记物提供的成比例降低的信号,在所有这些情况下的定量可以确定酶促产生的PIP3的量。PI3Kα或PI3Kα突变体的活性越高,则所产生的PIP3的量越大,而与固相结合的竞争者PIP3的量越少。与竞争者PIP3包含的标记物提供的信号的标准曲线比较可以评估PI3Kα或PI3Kα突变体的相对活性。
PI3Kα或PI3Kα突变体催化的反应优选通过将反应混合物中的一种或多种酶与ATP和PIP2(作为酶反应底物)一起提供而建立。在一个优选的实施方案中,将ATP添加至一种或多种酶并进行预孵育步骤。这样的预孵育优选在0℃至35℃的温度进行,更优选在15℃至30℃的温度,最优选在约20℃至约28℃的室温,特别是在25℃进行。预孵育步骤通常进行约5至20分钟,取决于温度和总体条件。
然后通过添加包含PIP2的底物溶液来启动酶促反应。作为酶促反应的底物,可以使用带有短侧链的水溶性PIP2(Gray等人,Anal Biochem 313(2):234-245(2003),Carson等人,Biochem J 409(2)):519-524(2008))。在这种情况下,所有试剂都存在于水相中。此外,可以使用脂质体膜中包含的并且携带长的天然脂肪链的“天然”PIP2(Lingaraj等人,JBiomol Screen 13(9):906-911(2008),Mandelker等人,Proc Natl Acad Sci USA 106(40):16996-17001(2009))。在这种情况下,反应混合物包含两个相,并且在膜和水之间的相间发挥酶活性,这甚至更好地模拟了细胞膜处酶促反应的生理微环境,因此是本发明的一个优选实施方案。
将包含酶或酶突变体和底物(在合适的溶液中,优选在缓冲溶液中)的反应混合物与ATP在与上文对于任选的预温育步骤指示的温度相同的温度再孵育一段合适的时间,优选5至20分钟,尤其是8至12分钟。反应终止后,将现在包括酶促产生的PIP3的混合物转移至与GST-GRP1功能化的固相接触。如上所述且本领域技术人员将很清楚的,竞争者PIP3可以更早地与固相接触,或者随后与反应混合物同时添加。测定与没有反应混合物的功能化固相所获得的较早信号相比或与为确定PIP3量而提供的标准曲线相比,竞争者PIP3的标记物或报告分子提供的信号及其减少程度,可以对酶促生产的PIP3定量。
该发明性的测定法允许在存在和不存在反应混合物中包含的潜在抑制剂或调控剂分子的情况下测量PI3Kα或PI3Kα突变体的活性。在本发明的上下文中,该测定法是确定此类潜在抑制剂或调控剂对蛋白质的作用以及因此确定其在医学尤其是在癌症治疗中的潜在用途的有价值的工具,如以上详细解释的。
已经概括地描述了本发明的各个方面,对于本领域技术人员而言显然的是,在不背离本发明的精神和范围的情况下可以进行许多修改和细微变化。
实施例
实施例1.用于生成式(II)的化合物的合成方案
2,6-双((((1H-苯并[d]咪唑-2-基)硫)甲基)吡啶的制备
2,6-双((((1H-苯并[d]咪唑-2-基)硫)甲基)吡啶的制备。在1H-苯并[d]咪唑-2-硫醇(100mg,0.67mmol)在EtOH的溶液中在氩气氛下加入NaOH(27mg,0.67mmol)。将反应混合物在25℃搅拌30分钟。接着,加入盐酸盐形式的2,6-双(氯甲基)吡啶(72mg,0.34mmol)在EtOH(1.7mL)中的溶液,并将该反应在65℃回流。4小时后,将反应冷却至25℃,并加入NaOH1N溶液(0.5mL)直至pH=9。将反应真空浓缩并将产物从H2O和MeOH中结晶(114mg,白色固体,85%产率)。
1H NMR(500MHz)25℃,DMSO:δ12.63(s,2H,-NH-),7.71(t,J=7.7Hz,1H,ArH),7.44(s,6H,ArH),7.11(dd,J=5.4,2.8Hz,4H,ArH),4.65(s,4H,-CH2-)。
MS:[M-H]- 计算值:402.1;[M-H]- 实验值:401.7
实施例2.用于产生式(III)的化合物的合成方案
N2,N6-二苄基吡啶-2,6-二甲酰胺(dicarboxamide)的制备
N2,N6-二苄基吡啶-2,6-二甲酰胺的制备。在苯甲胺(0.2mL,0.49mmol)的甲苯(3mL)溶液中,加入吡啶-2,6-二羰基二氯化物(50mg,0.25mmol)。将反应混合物在氩气氛下于25℃搅拌12小时。接下来,在反应混合物中加入1MNaOH水溶液(3mL),并用EtOAc萃取反应。将有机层用饱和NaCl水溶液洗涤,经Na2SO4干燥,并在减压下浓缩。产生的固体从甲苯中结晶以产生N2,N6-二苄基吡啶-2,6-二甲酰胺(60mg,70%产率)。
1H NMR(500MHz)25℃,DMSO:δ8.39(d,J=7.8Hz,2H,ArH),8.04(t,J=7.5Hz,1H,ArH),7.33–7.28(m,J=3.9Hz,10H,ArH),4.65(s,4H,-CH2-)ppm
MS:[M+H]+ 计算值:346.2;[M+H]+ 实验值:345.8
实施例3.用于产生式(IV)的化合物的合成方案
N2,N6-双(3-羟苯基)吡啶-2,6-二甲酰胺的制备
N2,N6-双(3-羟苯基)吡啶-2,6-二甲酰胺的制备。在3-氨基苯酚(54mg,0.49mmol)与Et3N(70μL,0.49mmol)的THF(1mL)溶液中,在-20℃添加吡啶-2,6-二羰基二氯化物(50mg,0.245mmol)的THF(2.5mL)溶液。将反应混合物在氩气氛下于25℃搅拌2小时。将反应混合物在减压下浓缩,并且将出现的固体从MeOH中结晶以产生N2,N6-双(3-羟苯基)吡啶-2,6-二甲酰胺(25mg,产率29%)。
1H NMR(500MHz)25℃,DMSO:δ10.90(s,2H,-NH-或-OH),9.53(s,2H,-NH-或-OH),8.38(d,J=7.6Hz,2H,ArH),8.29(t,J=7.6Hz,1H,ArH),7.47(s,2H,ArH),7.32(d,J=7.9Hz,2H,ArH),7.21(t,J=8.0Hz,2H,ArH),6.59(d,J=7.8Hz,2H,ArH)ppm
MS:[M+H]+ 计算值:350.1;[M+H]+ 实验值:349.7
实施例4.使用含PIP2的脂质体对PI3K-010进行体外无细胞PI3Kα活性测定。
为了评估具有式(II)的化合物(PI3K-010)的体外活性,使用含有PIP2的脂质体进行了PI3Kα活性测定(Gkeka等人,PLOS Comp Biol 2014)。在该测定中,PI3Kα产生的PIP3分子与生物素化的PIP3竞争结合重组GST-GRP1-PH结构域(氨基酸263-380),该结构域是在细菌中产生的,与包被有谷胱甘肽的96孔板结合。通过结合板的链霉亲和素-HRP的过氧化物酶活性估算生物素-PIP3的竞争量来进行定量,并为该蛋白质的活性提供了量度。将化合物与测定混合物的所有组分(PIP2除外)在25℃预孵育10分钟。在预孵育期结束时添加PIP2,从而启动激酶反应。
具有式(II)的化合物的IC50值
使用野生型PI3Kα蛋白以及含有H1047R突变的PI3Kα突变蛋白的logit-log图从剂量-应答曲线计算得出。
所有测定均在至少两个独立的实验中进行,每个浓度一式三份。将PIK-108和渥曼青霉素用作对照(Gkeka等人,2014J Phys Chem B)。与野生型PI3Kα相比,具有式(II)的化合物PI3K-010对突变PI3KαH1047R蛋白表现出11倍的抑制选择性(参见图1)。
接下来,进行低ATP(100μM)和高ATP(2mM)浓度的实验以鉴定PI3K-010是否为ATP竞争性抑制剂。我们发现ATP浓度仅轻微影响PI3K-010的IC50,因此该化合物可被视为非竞争性抑制剂(参见图2)。
实施例5.使用含PIP2的脂质体对PI3K-021进行体外无细胞PI3Kα活性测定。
为了评估具有式(III)的化合物(PI3K-010)的体外活性,使用含有PIP2的脂质体进行了PI3Kα活性测定(Gkeka等人,PLOS Comp Biol 2014)。在该测定中,PI3Kα产生的PIP3分子与生物素化的PIP3竞争结合重组GST-GRP1-PH结构域(氨基酸263-380),该结构域在细菌中产生,结合包被有谷胱甘肽的96孔板。通过结合板的链霉亲和素-HRP的过氧化物酶活性估算生物素-PIP3的竞争量来进行定量,并提供该蛋白质活性的量度。将化合物与测定混合物的所有组分(PIP2除外)在25℃预孵育10分钟。在预孵育期结束时添加PIP2,从而启动激酶反应。
具有式(III)的化合物的IC50值
使用野生型PI3Kα蛋白以及包含H1047R突变的突变PI3Kα蛋白的logit-log图从剂量-应答曲线计算得到。
所有测定均在至少两个独立的实验中进行,每个浓度一式三份。与野生型PI3Kα相比,具有式(III)的化合物PI3K-021对突变PI3KαH1047R蛋白显示出>100倍的选择性(图3)。对于突变体H1047R PI3Kα,发现PI3K-021的IC50为13.5μM,而对于WT,由于即使在PI3K-21的最高测试浓度下PIK-021对WT蛋白的抑制也非常低,因此无法估计确切的IC50值。通过外推,我们估算对于WT PI3Kα,PI3K-021的IC 50为>1000μM(参见图3)。
实施例6.使用含PIP2的脂质体对PI3K-024进行体外无细胞PI3Kα活性测定。
为了评估具有式(IV)的化合物(PI3K-024)的体外活性,使用含有PIP2的脂质体进行了PI3Kα活性测定(Gkeka等人,PLOS Comp Biol 2014)。在该测定中,PI3Kα产生的PIP3分子与生物素化的PIP3竞争结合重组GST-GRP1-PH结构域(氨基酸263-380),该结构域在细菌中产生,结合包被有谷胱甘肽的96孔板。通过结合板的链霉亲和素-HRP的过氧化物酶活性估算生物素-PIP3的竞争量来进行定量,并提供该蛋白质活性的量度。将化合物与测定混合物的所有组分(PIP2除外)在25℃预孵育10分钟。在预孵育期结束时添加PIP2,从而启动激酶反应。
具有式(IV)的化合物的IC50值
使用野生型PI3Kα蛋白以及含有H1047R突变的突变型PI3Kα蛋白的logit-log图从剂量-应答曲线计算得出。
所有测定均在至少两个独立的实验中进行,且每个浓度一式三份。具有式(IV)的化合物PI3K-024对WT和突变蛋白均表现出纳摩尔级的抑制作用(对WT的IC50=6nM,对突变H1047R PI3Kα蛋白的IC50=64nM)(参见图4)。
实施例7.对由乳腺癌MDA-MB-231细胞系或乳腺癌HCC1954细胞系的异位移植产生的异种移植物的PI3K-010或PI3K-021处理。
发明人评估了在皮下注射来自乳腺癌MDA-MB-231细胞系和乳腺癌HCC1954细胞系的细胞后携带异位异种移植物的小鼠上,具有式(I)的化合物(PI3K-010)和具有式(II)的化合物(PI3K-021)的体内活性,其中所述乳腺癌MDA-MB-231细胞系为野生型PIK3CA,乳腺癌HCC1954细胞系具有PIK3CA上的外显子20H1047R突变。为了移植,将八周龄的NOD/SCID小鼠使用异氟烷气体(4%)和氧气的混合物的稳定流麻醉,并将106个癌细胞皮下接种到其侧肋腹中,并每天进行监测直到肿瘤变得可触知(肿瘤体积mm3)。然后将小鼠随机分为两组用于PI3K-010或媒介物施用达两周时间段。通过将PI3K-010或PI3K-021与玉米油混合,然后每天两次以100mg/Kg剂量口服给药来实现施用。显示了平均重量+S.E.M(对于MDA-MB-231,n=7,对于HCC1954,n-5)。图5示出了手术回收的PI3K-010处理的或PI3K-021或未处理的(对照)异种移植物的总体外观。
实施例8.WAPCre/外显子20Pik3ca*/MMTV-Myc小鼠的微型PET/CT成像
在用PI3K-010化合物治疗乳腺癌的开始和结束时(两周),获得了WAPCre/外显子20Pik3ca*/MMTV-Myc小鼠的PET/CT图像(参见图6)。该化合物以口服方式(通过灌饲)以100mg/Kg的剂量给药。对照小鼠仅接受溶剂。乳腺癌残留物对18F-FDG吸收的减少是明显的。白色箭头指示乳腺的解剖部位。注意到膀胱中(示踪剂的***)以及心脏中18F-FDG的高浓度。为了进一步研究PI3K-010的作用,我们通过手术切除了乳腺肿瘤。使用抗细胞增殖标志物Ki67的抗体对异种移植物进行的免疫组织化学分析显示,与对照相比,治疗后肿瘤坏死并减少了增殖(增殖指数分别为15.0+3.3%和69.9+5.1%)。
实施例8.建立磷脂酰肌醇3-激酶α的新的基于膜的活性测定法。
该实施例描述了一种用于测量脂质PI3Kα活性的方法的开发,该方法非常稳健,易于实施,快速,廉价,不需要专门的设备并且可以在高通量模式下使用。
如上所述,该测定法的主要思路是基于催化反应的产物PIP3结合具有pleckstrin同源性(PH)结构域的蛋白质的高亲和力和特异性,所述具有pleckstrin同源性(PH)结构域的蛋白质例如磷酸肌醇同等型1通用受体(GRP1PH)。该测定法用于测定基态中PI3Kα野生型和致癌突变体H1047R和E545K的活性,以及在被磷酸化受体酪氨酸激酶生理激活时的活性。在验证测定法的过程中,测试了三种不同类型的PIP2底物,一种水溶性diC8PtdIns(4,5)P2和两种“脂质体”形式,其中不同量的长酰基侧链PIP2掺入了从HCT116细胞提取的天然脂质中,以便尽可能地模拟生理膜状态。该测定法还用于测试和评估几种“从头”合成的化合物,以发现突变体特异性抑制剂。
材料和方法
脂质体的制备
为了制备含PIP2的脂质体,从HCT116细胞制备脂质。HCT116是一种结直肠癌细胞系,其中PIK3CA基因在外显子20中带有H1047R突变。将提取的脂质与PIP2(包含长侧链,来自大脑,Avanti)混合,并在N2气流下干燥混合物。制备了两种脂质体制剂,其含有10%或50%的PIP2。样品完全干燥后,在N2气流下再放置30分钟,并在高速真空下进一步干燥1小时。然后,添加水溶液(20mM Tris pH=7.4、100mM KCl、1mM EDTA pH=8和1mM EGTA)并将脂质混合物在室温孵育1小时,伴随偶尔涡旋(每10分钟)。随后,将样品进行5次冷冻/解冻循环,然后在水浴中超声处理30分钟。最后,使用Avanti迷你挤出机(按照制造商的说明)将制备物挤出,并具有100nm的膜,从而产生直径小于100nm的单层小囊泡的均质制备物。
GST-GRP1结构域的表达和纯化
将GST-GRP1的cDNA转化到大肠杆菌BL21菌株(DE3)中。使用制造商标准规程在谷胱甘肽-琼脂糖4B(Amersham Pharmacia)上亲和纯化GST-GRP1。通过SDS-PAGE确定蛋白质的纯度。
PI3K激酶活性测定
将涂有谷胱甘肽的96孔板与封闭缓冲液(50mM Tris pH=7.4,150mM NaCl,0.05%Tween和0.2%明胶)在室温(RT)在摇动下孵育1小时。然后,向每个孔中加入1μg纯化的GST-GRP1,并在摇动下在RT孵育1小时。最后,将孔用洗涤缓冲液(50mM Tris pH=7.4,150mM NaCl和0.2%明胶)洗涤5次,每次洗涤步骤2分钟。并行地,在微管中设定PI3K反应,其通过添加5μl反应缓冲液(250mM Tris pH=7.4,10mM MgCl2),2.5μl ATP(100μM),2μlBSA(10μg/μl),1-2μlPI3K(2ng/μl),1μl所研究的化合物(抑制剂)和H2O至20μl的最终体积,并将混合物在25℃孵育10分钟(预孵育步骤)。通过添加5μl底物溶液(含40ng/μlPIP2)(总共200ng PIP2)来启动反应,并在25℃进行8至12分钟。通过添加75μl终止溶液终止反应,该终止溶液包含在洗涤缓冲液中的5mM EDTA,1%BSA,0.07%脱氧胆酸钠和0.3ng生物素化的diC8PtdIns(3,4,5)P3(生物素-PIP3),pH=8,然后将整个混合物转移至96孔板的孔中(该孔包含如上所述制备的GST-GRP1),并在摇动下于RT孵育1h(在此步骤中,PI3K反应的PIP3产物与生物素-PIP3竞争与GST-GRP1的结合)。将孔用洗涤缓冲液洗涤5次,每次2分钟,并加入链霉亲和素-HRP缀合物,并在摇动下于RT孵育40分钟。将孔洗涤5次,每次2分钟,并加入HRP底物(OPD,邻苯二胺)并温育1-20分钟(直到变成棕色)。使用ELISA读取器在492nm读取孔中溶液的吸光度。为了评估抑制剂或磷酸化的PDGFR肽或筛选新化合物,在PIP2底物的添加之前,在预温育步骤之前向PI3K反应混合物加入1或2μl的测试分子(在合适的缓冲液中)。作为对照,在相同条件下测试了等体积的溶剂的效果。
为了计算允许评估PI3K活性水平的通过酶促反应产生的PIP3的量(以AU计),制备了针对PIP3的A492nm标准曲线。为了生成标准曲线,即吸光度相对于PIP3分子的任意单位,使用了PIP3储备溶液,其通过在常规PI3K反应条件下将PIP2与PI3K孵育制备。该最终制备物用作PIP3分子的标准品(以AU计)用于生成标准曲线。该标准曲线遵循PI3K产生的PIP3和b-PIP3之间对GST-GRP1结合的拮抗性抑制的预期双曲线概况。尽管使用上述标准曲线仅允许以任意单位(AU)评估PIP3分子的量,但此测量足以用于比较性体外研究,例如着手于调节PI3K活性的分子机制的实验,或旨在鉴定PI3K抑制剂的小分子筛选研究。
结果
新的PI3K激酶α活性测定法的原理
为了建立一个简单的、基于膜的PI3Kα活性测定法,我们利用了以下事实:PI3Kα的催化活性产物膜脂质PIP3以高亲和力和选择性结合GRP1的PH结构域,而反应的底物PIP2反应仅最少地与GRP1结合(Lindsay等人,J Cell Sci119:5160-5168(2006):Ferguson等人,Mol Cell 6:373-384(2000);Fleming等人,Biochem J 51:173-182(2000))。因此,为了测定PI3Kα的活性,我们使用了与GST融合的GRP1的PH结构域(为简便起见,从此处起称为GST-GRP1),其结合于谷胱甘肽包被的96孔板,以捕获由PI3K产生的PIP3分子。为了量化产生的PIP3的量,我们采用了一种基于竞争的间接测定法。为此,在酶促反应终止后,将生物素-PIP3外源添加到含有PI3Kα反应产物的混合物中(充当GRP1和PIP3之间结合的竞争者),然后将整个混合物与96孔板的孔一起孵育(图7);在此孵育过程中,PIP3(PI3K反应的产物,以红色显示)和生物素-PIP3(外源添加)都以竞争性方式与GST-GRP1形成独立的复合物。最后,将链霉亲和素-HRP加入孔中,以评估结合的生物素-PIP3的量。当存在PI3K时,PI3Kα活性越高,产生的PIP3量越多,将结合于板的生物素-PIP3和链霉亲和素-HRP的量就越少,这导致492nm处的吸光度值越低(图7)。相反,在PI3Kα抑制剂的存在下,PIP3的水平与抑制剂的有效性成比例地降低,这导致生物素-PIP3和链霉亲和素-HRP与板孔的结合更高,从而导致在492nm处有更高的吸光度。因此,抑制剂越强,吸光度越高。492nm处吸光度相对于增加的PIP3水平的标准曲线允许评估PI3Kα的以任意单位计的相对活性(进一步参见下文,图12)。
PI3K活性测定法条件的建立
为了实现低噪音,最大可能的动态范围和特异性,已经对测定法的所有试剂和条件进行了优化。首先,优化了应与板结合以捕获足够量的生物素-PIP3的GST-GRP1的量,以在492nm处产生高吸光度。GST-GRP1在细菌中表达,并使用谷胱甘肽包被的珠进行纯化(图8a)。为了确定产生足够高信号的GST-GRP1的最佳量,将增加量的GST-GRP1添加到谷胱甘肽包被的板中,然后与生物素-PIP3、链霉亲和素-HRP一起孵育并在492nm处测量吸光度。如图8a所示,GST-GRP1的最佳量为3μg,因为更高量的蛋白质(10μg)未显著提高492nm处的吸光度。
然后,优化了测定中应使用的b-PIP3的量。如预期的,我们观察到添加到板上的b-PIP3的量越高,吸光度就越高(图9)。在测试的量中,0.3μg的b-PIP3的量产生的吸光度足够高,而更高量的b-PIP3未急剧提高信号(图9)。由于测定是基于外源性b-PIP3和PI3K产生的PIP3之间的竞争,因此测定中添加的b-PIP3越高(超出产生可接受信号所需的量),就需要越大量的PI3K和PIP2用于测定混合物中的竞争,这将增加筛选化合物库的成本。因此,选择0.3μg的量用于随后测定。
接下来,从底物PIP2开始确定PI3K反应中使用的试剂的最佳浓度。尽管可将具有短侧链的PIP2的可溶形式(diC8)用于测定法中,但是本发明人在此试图采用在脂质体膜中的天然PIP2(其包含长的天然脂肪链)作为底物。在这种情况下,在包含两相(水和膜)的反应混合物中,酶活性施加在膜和水之间的相间,这更好地模拟了细胞膜处酶促反应的生理微环境。首先,考虑到PIP2在某种程度上与GST-GRP1结合(尽管GST-GRP1对PIP3具有高度特异性(Lietzke等人,Mol Cell 6(2):385-394(2000),He等人,J Lipid Res 49(8):1807-1815(2008)),我们测试了PIP2是否干扰生物素-PIP3与GST-GRP1的结合。当将PIP2用作脂质体膜的唯一组分时(没有其他脂质),即使在最低的PIP2浓度(50ng/100μl反应)下,信号也受到实质性抑制(图10a),这可能是由于PIP2和生物素-PIP3之间对GST-GRP1结合的竞争性抑制所致(Corbin等人,Biochemistry 43(51):16161-16173(2004),He等人,J Lipid Res49(8):1807-1815(2008),Lai等人,JMol Biol 425(17):3073-3090(2013))。另一方面,当将PIP2掺入到脂质体中与从HCT116细胞提取的天然脂质一起时,PIP2对信号的干扰显著降低(将图10b的含有在脂质体中浓度为10%的200ng PIP2的样品与图10a的相应样品比较),这可能是由于PIP2在与其他脂质一起掺入膜中时,PIP2的构象、可用性和/或微环境不同。当在脂质体中使用高浓度的PIP2(50%)时,尽管存在脂质体,但生物素-PIP3与GRP1的结合受到抑制,这通过添加低于CMC的浓度的脱氧胆酸钠基本上得以挽救。因此,在所有后续实验中,将底物PIP2整合在脂质体膜中,该脂质体膜是使用从细胞膜提取的脂质制备的,同时加入脱氧胆酸盐以减少脂质与GRP1的非特异性结合。
最终,发明人到达建立测定法的最后一步,在该步骤中他们确定了相对于不同量的底物PIP2(在脂质体中制备)的PI3K水平的最佳组合。测试脂质体中分别以10%PIP2与50%PIP2的两种不同脂质比率的稳定量的PIP2(200ng),发现高浓度的PIP2(脂质体中50%)对于PI3K实现高水平的活性是关键性的。此外,当将PIP2的可溶形式用作底物(diC8PtdIns(4,5)P2)(其中酯的烃链较短)时,需要多达2μg PIP2以获得用脂质体中50%浓度的200ng PIP2所达到的活性的不到一半。因此,与脂质体中的脂质PIP2(50%)相比,PIP2的水溶性形式是差得多的底物。因此,脂质体中浓度50%的PIP2脂质形式是为随后实验所选的形式。
为了鉴定测定法的最佳量的PIP2(以脂质体的50%形式存在),我们测试了增加量的PIP2与两种不同量的PI3K(2和4ng)的组合。如图11b中所示,在200ng的PIP2时,反应达到平台,即产生的PIP3的水平足够高以至于几乎完全阻断生物素-PIP3与GST-GRP1的结合。由于底物需要过量以排除成为反应限制因素的可能性,因此在所有后续实验中均使用200ng的底物。
鉴于该测定法是基于产物(PIP3)与生物素-PIP3之间与GST-GRP1结合的竞争,因此,当存在PIP3时,吸光度的下降预期不会与PI3K产生的PIP3量成正比。因此,需要一条标准曲线,以将通过测定确定的吸光度值转换为PI3K产生的PIP3的量。如预期的,实验标准曲线(492nm处的吸光度相对于外源添加的PIP3的量)遵循双曲线概况,该曲线对于其中拮抗剂(PIP3,由PI3K产生)竞争性地去除了负责测量信号(在492nm处的吸光度)的激动剂(生物素-PIP3)的测定法而言是典型的。
建立了PI3K活性测定法的条件后,可以以任意单位评估PI3K的活性,我们着手验证该方法的特异性。首先,我们测试了该测定法是否满足酶促反应的标志,即对酶的剂量和反应的持续时间的依赖性。实际上,定量的酶活性是PI3K剂量依赖性的(图13a)以及时间依赖性的(图13b)。作为测定法的进一步验证测试,我们使用了著名的PI3K激酶抑制剂来测试其对酶活性的影响。图14中的数据表明,已知的抑制剂(如渥曼青霉素、LY-294002和PIK-108)的IC50值与文献报道的一致(图14)。
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Claims (15)
6.一种药物组合物,其包含权利要求1-5中任一项的化合物,任选地还包含一种或多种其他治疗剂。
7.权利要求6的药物组合物,其中所述一种或多种其他治疗剂选自下组:
10-羟基喜树碱,17-烯丙基氨基-格尔德霉素,2-甲氧基抗霉素A3,3,4-二氯异香豆素,4-羟基苯基视黄酰胺(4-Hydroxyphenylretinamide),9-顺式视黄酸,阿比特龙(Abiraterone),曲妥珠单抗美坦(Ado-Trastuzumab Emtansine),阿霉素,阿法替尼(Afatinib),N-(3-氯苯基)-6,7-二甲氧基喹唑啉-4-胺,2-氨基-4-(1H-吲哚-5-基)-1,1,3-三氰基丁-1,3-二烯,阿地白介素,阿仑单抗(Alemtuzumab),氨磷汀,阿那曲唑(Anastrozole),茴香霉素,阿非迪霉素(Aphidicolin),三氧化二砷,天冬酰胺酶菊欧文氏杆菌(Erwinia chrysanthemi),阿瓦斯汀,阿昔替尼(Axitinib),N-[2(S)-(2(R)-2-氨基-3-巯基丙基氨基)-3-甲基丁基]-L-苯丙氨酰-L-蛋氨酸三氟乙酸盐,卡介苗,双酚A二缩水甘油醚,苯达莫司汀,β-拉帕醌,桦木酸,贝伐单抗,贝沙罗汀(Bexarotene),比卡鲁胺(Bicalutamide),双苯甲酰亚胺,博来霉素,硼替佐米,博舒替尼(Bosutinib),布舍瑞林(Buserelin),白消安,卡巴他赛,卡博替尼-S-苹果酸,Calpeptin,喜树碱,咖啡酸苯乙酯,卡培他滨,卡普雷萨(凡德他尼(Vandetanib)),卡铂,卡铂,卡非佐米,卡莫司汀,西妥昔单抗,苯丁酸氮芥,环格列酮(Ciglitazone),顺铂,氯膦酸盐,氯法拉滨,卡博替尼(Cometriq),克唑替尼(Crizotinib),姜黄素(Curcumin),环[Arg-Gly-Asp-D-Phe-Val],环己酰亚胺,环杷明,环磷酰胺,环孢菌素A,环丙孕酮,阿糖胞苷,D12-***素J2,达布拉非尼(Dabrafenib),达卡巴嗪,更生霉素,达沙替尼,道诺霉素,地加瑞克(Degarelix),地诺单抗(Denosumab),***,多西他赛,多柔比星(Doxorubicin),依布硒啉(Ebselen),玫瑰树碱(Ellipticine),恩杂鲁胺(Enzalutamide),表柔比星,厄洛替尼,依托泊苷,依维莫司,依西美坦,氟达拉滨,氟尿嘧啶,氟他胺,亚叶酸,氟维司群(Fulvestrant),吉非替尼,格尔德霉素(Geldanamycin),吉西他滨,染料木黄酮(Genistein),姜醇,卡莫司汀植入剂(Gliadel Wafer),胶霉毒素,戈瑟瑞林,2-氯-5-硝基苯甲酰苯胺,2-氨基-6-溴-α-氰基-3-(乙氧羰基)-4H-1-苯并吡喃-4-乙酸乙酯,Hinokitiol,羟基脲,索布佐生(Sobuzoxane),伊达比星,异环磷酰胺,伊马替尼,吲哚美辛,伊匹木单抗(Ipilimumab),伊立替康,伊沙匹隆(Ixabepilone),兰瑞肽(Lanreotide),拉帕替尼,来那度胺,来曲唑,甲磺酸乐伐替尼(Lenvatinib),乐卫玛(Lenvima),亚叶酸(Leucovorin),亮丙瑞林(Leuprolide),洛莫司汀,甲孕酮,甲地孕酮,美法仑,Mepesuccinate,巯基嘌呤,Mesna,甲氨蝶呤,甲氧基维拉帕米,苄氧羰基-L-亮氨酰-L-亮氨酰-L-leucinal,丝裂霉素C,米托蒽醌,N,N-二甲基鞘氨醇,奈拉滨(Nelarabine),尼洛替尼(Nilotinib),纳武单抗(Nivolumab),奥曲肽,奥法木单抗(Ofatumumab),寡霉素A,Omacetaxine,奥沙利铂,紫杉醇,帕米膦酸钠(Pamidronate),帕尼单抗(Panitumuma),帕唑帕尼(Pazopanib),培门冬酶(Pegaspargase),培美曲塞,派姆单抗(Pembrolizumab),帕妥珠单抗,Pifithrin,普乐沙福(plerixafor),鬼臼毒素,泊马度胺,波纳替尼(Ponatinib),强的松,2,2-双(羟甲基)-1-氮杂双环[2.2.2]辛-3-酮,丙卡巴嗪,二氯化镭223,雷替曲塞,雷帕霉素,重组人***瘤病毒(HPV)二价疫苗,重组HPV四价疫苗,重组HPV二价,疫苗,重组HPV四价疫苗,重组干扰素α-2b,瑞戈非尼(Regorafenib),白藜芦醇,所有反式视黄酸,Rheumatrex,利妥昔单抗,咯利普兰(Rolipram),Roscovitine,粗糠紫毒素(Rottlerin),紫草素(Shikonin),Sipuleucel-T,西罗莫司,索拉非尼,鞘氨醇,裂殖霉素(Splitomycin),星形孢菌素,己烯雌酚(Stilboestrol),链脲菌素,3-(4-二甲基氨基苄亚甲基)-2-吲哚二酮,3-[[(4-二甲基-氨基)苯基]亚甲基]-1,3-二氢-2H-吲哚-2-酮,硫化舒林酸,舒尼替尼,他莫昔芬,替莫唑胺,替莫罗莫司(Temsirolimus),沙利度胺,托泊替康,托瑞米芬,曲美替尼,曲妥珠单抗,曲古抑菌素-A,三氟拉嗪,4-[(E)-2-(5,6,7,8-四氢-5,5,8,8-四甲基-2-萘基)-1-丙烯基]苯甲酸,3,4-二羟基-α-氰基硫代肉桂酰胺,(3-羟基-4-硝基苄亚甲基)丙二腈,凡德他尼(Vandertanib),丙戊酸,维莫非尼(Vemurafenib),维拉帕米,长春碱,长春新碱,长春瑞滨,渥曼青霉素,4-氯-6-(2,3-二甲代苯氨基)-2-嘧啶基硫代乙酸,阿柏西普(Ziv-Aflibercept),唑来膦酸,其盐及其组合,
优选地选自下组:阿比特龙,曲妥珠单抗美坦,阿法替尼,Afinitor(依维莫司),阿那曲唑,阿瓦斯汀,贝伐单抗,卡巴他赛,卡培他滨,卡铂,卡莫司汀,顺铂,克唑替尼,环磷酰胺,地加瑞克,地诺单抗,多西他赛,多柔比星,恩扎鲁胺,表柔比星,厄洛替尼,依托泊苷,依维莫司,依西美坦,氟尿嘧啶,氟维司群,吉非替尼,吉西他滨,伊沙匹隆,拉帕替尼,来曲唑,亮丙瑞林,洛莫司汀,甲地孕酮,甲氨蝶呤,丝裂霉素C,紫杉醇,帕米膦酸,培美曲塞,帕妥珠单抗,强的松,二氯化镭223,Sipuleucel-T,舒尼替尼,他莫昔芬,替莫达(Temodar),替莫唑胺,托泊替康,托瑞米芬,曲妥珠单抗,卡博替尼-S-苹果酸,卡普雷萨(凡德他尼(Vandetanib)),卡博替尼(卡博替尼-S-苹果酸),盐酸多柔比星,伊匹木单抗,甲磺酸乐伐替尼,Nexavar(甲苯磺酸索拉非尼),纳武单抗,凡德他尼,Yervoy(伊匹木单抗),其盐及其任意组合。
8.权利要求6-7中任一项的药物组合物,其进一步包含一种或多种其他治疗剂,所述其他治疗剂选自下组:
乙酰水杨酸,二氟尼柳(Diflunisal),水杨酰水杨酸,布洛芬,右布洛芬,萘普生,非诺洛芬(Fenoprofen),酮洛芬(Ketoprofen),右旋酮洛芬(Dexketoprofen),氟比洛芬(Flurbiprofen),奥沙普嗪(Oxaprozin),洛索洛芬(Loxoprofen),吲哚美辛(Indomethacin),托美汀(Tolmetin),舒林达克(Sulindac),依托度酸(Etodolac),酮咯酸(Ketorolac),双氯芬酸(Diclofenac),萘丁美酮(Nabumetone),吡罗昔康(Piroxicam),美洛昔康(Meloxicam),替诺昔康(Tenoxicam),屈昔康(Droxicam),氯诺昔康(Lornoxicam),伊索昔康(Isoxicam),甲芬那酸(Mefenamic acid),甲氯芬那酸(Meclofenamic acid),氟芬那酸(Flufenamic acid),托芬那酸(Tolfenamic acid),塞来昔布(Celecoxib),罗非考昔(Rofecoxib),Valdecosib,帕瑞昔布(Parecoxib),鲁米昔布(Lumiracoxib),依托昔布(Etoricoxib),非罗考昔(Firocoxib),尼美舒利(Nimesulide),利克飞龙(Licofelone),H哈巴苷(Hharpagide),赖氨酸氯尼辛,其药学可接受的盐,及其组合,优选地选自下组:塞来昔布,罗非考昔,Valdecosib,帕瑞昔布,鲁米昔布,依托昔布,非罗考昔,其药学可接受的盐,及其组合。
9.权利要求1-5中任一项的化合物或权利要求6-8中任一项的药物组合物,其用于医学,优选用于治疗或预防哺乳动物的癌性疾病,其中所述哺乳动物优选为人。
10.根据权利要求9的用途的化合物或药物组合物,其中所述癌性疾病易感于PI3Kα突变和/或过度活化,和/或扩增和/或失调。
11.根据权利要求9-10中任一项的用途的化合物或药物组合物,其中所述癌性疾病选自下组:急性单核细胞白血病,急性髓性白血病,急性骨髓单核细胞白血病,急性早幼粒细胞白血病,成人T细胞白血病,成人T细胞淋巴瘤,星形细胞瘤,非典型类癌肺癌,基底细胞癌,B急性淋巴细胞白血病,B细胞急性成淋巴细胞性白血病/淋巴瘤,膀胱癌,脑癌,乳腺癌,支气管癌,伯基特氏淋巴瘤,胆管癌,原发性来源未知的癌,***,慢性骨髓增生性病症,结肠癌,弥漫性大细胞淋巴瘤,子宫内膜癌,室管膜瘤,食道癌,胃癌,胶质瘤,胶质母细胞瘤,头颈癌,血管外皮细胞瘤,肝细胞癌,霍奇金氏淋巴瘤,卡波济肉瘤,肾癌,大细胞神经内分泌癌,大颗粒性淋巴细胞白血病,白血病,肝癌,肺癌,淋巴瘤,髓母细胞瘤,黑素瘤,多发性骨髓瘤,骨髓增生异常综合征,鼻咽癌,神经母细胞瘤,NK细胞瘤,非霍奇金氏淋巴瘤,食道鳞状细胞癌,骨肉瘤,卵巢癌,胰腺癌,外周T细胞白血病,原发性浆细胞白血病,***癌,肾透明细胞癌,视网膜母细胞瘤,横纹肌肉瘤,肉瘤,小细胞肺癌,T-细胞急性成淋巴细胞白血病,T-细胞急性成淋巴细胞淋巴瘤,睾丸癌,胸腺瘤,甲状腺癌,脐尿管癌,子宫癌,***癌及其组合,
优选选自下组:B急性淋巴细胞白血病,伯基特氏淋巴瘤,弥漫性大细胞淋巴瘤,多发性骨髓瘤,原发性浆细胞白血病,非典型类癌肺癌,膀胱癌,脑癌,乳腺癌,***,结肠癌,子宫内膜癌,胃癌,胶质母细胞瘤,头颈癌,肝细胞癌,大细胞神经内分泌癌,肝癌,髓母细胞瘤,黑素瘤,神经母细胞瘤,食道鳞状细胞癌,骨肉瘤,卵巢癌,垂体癌,***癌,肾透明细胞癌,视网膜母细胞瘤,横纹肌肉瘤,小细胞肺癌,结肠腺癌,肺腺癌,***腺癌,脐尿管腺癌,***腺癌,乳腺腺癌,食道腺癌,支气管腺癌,胰腺腺癌,胃肠道腺癌,子宫内膜腺癌,卵巢腺癌,胃腺癌,肝腺癌,甲状腺腺癌,头颈腺癌,膀胱腺癌和胃肠道癌;及其组合,优选地其中所述癌性疾病是胰腺导管腺癌,乳腺腺癌,***腺癌,或肺腺癌,子宫内膜腺癌,卵巢腺癌,胃腺癌,肝腺癌,甲状腺腺癌,头和颈腺癌,膀胱腺癌,和胃肠道腺癌及其组合。
15.一种用于测定PI3Kα或PI3Kα突变体活性的方法,所述方法包括:
a)提供固相,所述固相通过将GST-GRP1分子固定在其上而被功能化,
b)进行PI3Kα或PI3Kα突变体催化的酶反应以将PIP2转化为PIP3,
c)加入带有可检测标记或报告分子的竞争者PIP3,以及
d)基于步骤b)中获得的与竞争者PIP3竞争结合所述功能化固相的PIP3的量来测定酶活性。
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