CN117159721A - 用于联合治疗的抗肿瘤药物组合物 - Google Patents
用于联合治疗的抗肿瘤药物组合物 Download PDFInfo
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- CN117159721A CN117159721A CN202311059813.3A CN202311059813A CN117159721A CN 117159721 A CN117159721 A CN 117159721A CN 202311059813 A CN202311059813 A CN 202311059813A CN 117159721 A CN117159721 A CN 117159721A
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Abstract
本申请涉及用于联合治疗的抗肿瘤药物组合物,其包含(a)阿兹夫定或其药用盐、前药、水合物、溶剂化物或同位素标记的类似物和(b)PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂或其药用盐、前药、水合物、溶剂化物或同位素标记的类似物。
Description
技术领域
本申请涉及药物化学领域,具体地涉及用于联合治疗的抗肿瘤药物组合物。
背景技术
哺乳动物雷帕霉素靶蛋白(mTOR)是一种非典型丝氨酸/苏氨酸蛋白激酶,是细胞内合成和分解代谢等细胞功能的主要信号传递分子。mTOR信号通路与营养、能量状态和生长因子有着密切的关系。它调节包括自体吞噬、蛋白质、脂类、溶酶体合成和能量代谢、细胞骨架组建、细胞存活等多个细胞过程。由于mTOR在细胞中的重要作用,异常或失调的mTOR信号传递能导致人类疾病(例如癌症)的发生。因此mTOR信号通路逐渐成为设计抗癌药物的一个重要靶点。
PI3K/Akt/mTOR信号通路活化与多种肿瘤发生密切相关。在脑胶质瘤、乳腺癌、卵巢癌中,mTOR能够加速细胞周期,减少细胞凋亡,并促进肿瘤细胞的迁移。mTOR的活化起始于一些被配体激活的细胞表面上的生长因子受体,例如表皮生长因子受体和类胰岛素生长因子-1和-2(IGF-1和-2)。受体的激活导致PI3K激酶的激活,从而导致下游效应Akt蛋白的激活。Akt是一种能在多层次上调控细胞存活的调控因子。Akt磷酸化后抑制下游TSC1/2复合物,从而导致mTOR被Rheb激活。在PI3K/Akt及PEN/Akt和Ras/Erk1/2的信号通路的下游,TSC1/2复合物为调节mTOR的激活起着关键性的作用。
mTOR抑制剂药物的研发已取得重大进展。雷帕霉素是第一个被发现的mTOR抑制剂,在多种癌症模型中表现出较好的抑癌效果。虽然已经开发了具有更好药理学特性的雷帕霉素类似物,然而,临床上能应用的雷帕霉素类似物却仅局限在少数几种癌症上。Akt是癌细胞存活的一个重要激酶,而mTORC2可直接磷酸化Akt。这一重要发现为mTORC2在抗癌方面的研究提供了新的思路,并且也促进了同时作用于mTORC1和mTORC2两个靶点的第二代抗癌药物的研发。在癌细胞中同时抑制两个mTOR复合体(mTORC1和mTORC2)的活性有更广泛和更有效的抗癌作用。
国际申请WO2015074516A1公开了化合物1(实施例18),化学名为1-((1S,4S)-4-羟基环己基)-3-甲基-8-(6-(1-甲基-1H-吡唑-4-基)吡啶-3-基)-1H-咪唑并[4,5-c]喹啉-2(3H)-酮,其为蛋白激酶PI3K/mTORC1/mTORC2抑制剂。
阿兹夫定(化合物2,简写为FNC)作为一种嘧啶核苷药物,具有广谱抗病毒活性。它具有作为核苷逆转录酶抑制剂和辅助蛋白Vif(病毒感染因子)抑制剂的双靶点作用机制。专利ZL200710137548.0(实施例15)公开了阿兹夫定结构信息。阿兹夫定能够选择性地进入HIV-1靶细胞外周血单核细胞中的CD4细胞或CD14细胞,发挥抑制HIV、HCV、EV71等RNA病毒复制的功能。
阿兹夫定通过抑制RNA依赖性聚合酶来抑制阳性RNA病毒,如HCV、EV、SARS-COV-2、HBV和逆转录病毒(包括HIV)。它还可以抑制人类逆转录转座子中的这种酶(逆转录酶),包括人类内源性逆转录病毒(HERV)。由于反转录转座子的激活可能是持续的癌症基因组不稳定的主要因素,因此具有更高的肿瘤侵袭性,因此阿兹夫定有可能提高多种抗癌疗法的功效。此外,阿兹夫定还通过抑制恶性细胞的粘附、迁移、侵袭和增殖而显示出其他方面的抗癌活性。据报道,它还参与细胞周期停滞和细胞凋亡,从而通过不同途径抑制癌症的进展。阿兹夫定是一种细胞周期非特异性药物,可导致G1/S或G2/M期细胞周期停滞并诱导细胞凋亡。
阿兹夫定作为核苷类药物存在潜在抗肿瘤活性,可以与细胞内部产生的核苷酸竞争并入DNA和RNA链,从而导致肿瘤细胞内核苷酸合成减弱,并干扰肿瘤细胞的生长和分裂。调节免疫系统可能是阿兹夫定的另一个重要抗肿瘤机制。专利ZL200710137548.0中描述了2’-氟-4’-叠氮-核苷类似物阿兹夫定对多种人癌细胞及动物移植性肿瘤均具有明显的抑制作用。骨髓抑制是导致临床肿瘤化疗失败的最重要的因素之一。阿兹夫定在有效剂量的情况下对动物骨髓造血功能无明显影响,而5-Fu和DDP则有明显的抑制作用。阿兹夫定显示出低细胞毒性,因此意味着治疗的可接受的副作用。
肿瘤的发病机制复杂,而治疗肿瘤的药物种类繁多,普遍存在毒副作用大、容易对患者产生耐药等缺点。单药对于肿瘤的抑制作用已经不能满足严格的治疗要求。为了克服耐药,实现更早期、更深度的疾病缓解,延长疾病缓解时间和患者生存时间,积极探索不同形式的联合用药方案,是抗肿瘤药物研发的必然方向。
发明内容
针对上述现有技术的缺点,本发明的目的是提供一种核苷类逆转录酶和辅助蛋白Vif(病毒感染因子)双重抑制剂和蛋白激酶PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂的组合作为抗肿瘤药物的用途,其优点在于核苷类逆转录酶和辅助蛋白Vif(病毒感染因子)双重抑制剂和蛋白激酶PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂的协同作用,取得的抗肿瘤效果优于单一用药,对于肿瘤体积的抑制具有显著作用。
在一个方面,本发明提供了一种药物组合物,其包含:
(a)核苷类逆转录酶和辅助蛋白Vif(病毒感染因子)双重抑制剂或其药用盐、前药、水合物、溶剂化物或同位素标记的类似物,以及
(b)PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂或其药用盐、前药、水合物、溶剂化物或同位素标记的类似物。
在一些实施方案中,核苷类逆转录酶和辅助蛋白Vif(病毒感染因子)双重抑制剂或其药用盐、前药、水合物、溶剂化物或同位素标记的类似物为阿兹夫定(FNC,专利ZL200710137548.0中公开的化合物2(实施例15)):
在一些实施方案中,PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂选自PI3K抑制剂、ATR抑制剂、mTOR抑制剂,PI3K和mTOR双重抑制剂,PI3K和ATR双重抑制剂,ATR和mTOR双重抑制剂,以及PI3K、ATR和mTOR三重抑制剂。
在一些实施方案中,PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂为ATR抑制剂。在具体实施方案中,ATR抑制剂选自:VE-821、Berzosertib(VE-822,M6620,VX-970)、M4344(VX-803)、Ceralasertib(AZD6738)、M1774、ATRN-119、IMP9064、RP-3500、ART-0380、Elimusertib、AZD-1390、M-4076、XRD-0394。
在一些实施方案中,PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂为mTOR抑制剂。在具体实施方案中,mTOR抑制剂选自:依维莫司、雷帕霉素(西罗莫司)、MHY1485、Torin 1、AZD-8055、Dactolisib(BEZ235)、Sapanisertib(INK-128,MLN0128,TAK-228)、Temsirolimus(替西罗莫司)、Torin 2、Torkinib、Omipalisib(GSK2126458)、PI-103、Vistusertib(AZD2014)、PF-04691502、Samotolisib、GNE-493、PKI-179、PQR626、WYE-687、DS-7423、MHY-1685、GNE-477。
在一些实施方案中,PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂为PI3K抑制剂。在具体实施方案中,PI3K抑制剂选自:Aliqopa(Copanlisib)、BYL719、VS-5584、GSK2126458(Omipalisib)、GSK1059615、Bimiralisib(PQR309)、PQR530、BGT226(NVP-BGT226maleate)、Apitolisib(GDC-0980;GNE390;RG7422)、GSK2636771、LAS195319、HMPL-689、Dactolisib(BEZ235)、Pictilisib(GDC-0941)、Eganelisib(IPI549)、Duvelisib(IPI-145)、Samotolisib(LY3023414)、Taselisib(GDC-0032)、PI-103、Copanlisib(BAY 80-6946)、GDC-0077(RG6114)、Buparlisib(BKM120,NVP-BKM120)、PF-04691502、AZD8186、PKI-402、Voxtalisib(XL765)。
在一些实施方案中,PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂或其药用盐、前药、水合物、溶剂化物或同位素标记的类似物为1-((1S,4S)-4-羟基环己基)-3-甲基-8-(6-(1-甲基-1H-吡唑-4-基)吡啶-3-基)-1H-咪唑并[4,5-c]喹啉-2(3H)-酮(国际申请WO2015074516A1中公开的化合物1(实施例18)):
在另一个方面,本发明的药物组合物还包含免疫治疗剂,其选自PD-1阻断剂或PD-L1阻断剂或CTLA-4阻断剂。
在一些实施方案中,免疫治疗剂选自PD-1抗体或其抗原结合片段、PD-L1抗体或其抗原结合片段、可溶性PD-1或CTLA-4抗体或其抗原结合片段。
在一些实施方案中,本发明的药物组合物还可以包含另外的用于预防和/或治疗癌症或肿瘤的药物(诸如小分子、多肽、核酸、抗体、抗体偶联药物)。
在一些实施方案中,用于预防和/或治疗癌症或肿瘤的药物选自抗体偶联药物,其代表性实例可以包括但不限于恩美曲妥珠单抗(Trastuzumab emtansine)、维布妥昔单抗(Brentuximab Vedotin)、奥加伊妥珠单抗(brentuximab vedotin,BV)、维迪西妥单抗(Disitamab Vedotin)、戈沙妥珠单抗(sacituzumab govitecan)、德卢替康-曲妥珠单抗(Trastuzumab Deruxtecan)或其任意组合。在另一个方面,本发明还提供了一种核苷类逆转录酶和辅助蛋白Vif(病毒感染因子)双重抑制剂和PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂联合治疗疾病的方法,所述方法包括向有需要的患者施用本发明的组合物。
在另一个方面,本发明还提供了上述药物组合物在制备用于治疗疾病的药物中的用途。
在一些实施方案中,所述疾病选自癌症或肿瘤。癌症和肿瘤的代表性实例包括,但不限于,皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、肾癌、肾实质癌、宫颈癌、子宫体癌、子宫内膜癌、绒毛膜癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤(诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤)、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、白血病、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤和浆细胞瘤。
在一些实施方案中,所述癌症和肿瘤选自中晚期肿瘤、复发难治性肿瘤、经化疗药物治疗失败和/或复发肿瘤、经放疗失败和/或复发肿瘤、经靶向药物治疗失败和/或复发肿瘤、以及经免疫治疗失败和/或复发肿瘤。
作为本发明的最优选技术方案,本发明所涉及的联合用药将阿兹夫定(化合物2)和PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂(化合物1)结合起来,可以抑制许多具有致癌作用的病毒的活性。此外,作为核苷酸类似物,相比单独给药化合物2或单独给药化合物1,联合用药表现出癌细胞生长和癌细胞活跃增殖的更强抑制,其穿透合成的核酸链并导致链终止,从而诱导肿瘤细胞的凋亡。同时,联合用药具有较高的生物安全性,具有比单独用药更强的抗肿瘤活性,克服单药的耐药性,为肿瘤的治疗提供了新的策略和思路。
附图说明
图1示出了化合物1联合化合物2在HCT-116模型上的药效作用。
图2示出了化合物1联合化合物2在MKN45模型上的药效作用。
具体实施方式
定义
如本文中使用的,术语“联合”是一种给药方式,是指在一定时间期限内给予至少一种剂量的阿兹夫定和至少一种剂量的PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂和/或至少一种剂量的PD-1阻断剂或PD-L1阻断剂或CTLA-4阻断剂,其中两种或三种物质都显示药理学作用。所述时间期限可以是一个给药周期内,优选地4周内、3周内、2周内、1周内或24小时以内,更优选地12小时以内。可以同时或依次给予阿兹夫定和PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂和/或PD-1阻断剂或PD-L1阻断剂或CTLA-4阻断剂。这种期限包括这样的治疗,其中通过相同给药途径或不同给药途径给予阿兹夫定和PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂和/或PD-1阻断剂或PD-L1阻断剂或CTLA-4阻断剂。本发明的联合给药方式选自同时给药、独立地配制并共同给药或独立地配制并相继给药。
如本文中使用的,术语“药用盐”是指所公开的化合物的衍生物,其中母体化合物通过将现有酸或碱部分转化为其盐形式而进行改性。药用盐的实例包括,但不限于,与无机酸诸如盐酸、氢溴酸、磷酸和硫酸的盐,以及与有机羧酸和磺酸诸如乙酸、三氟乙酸、丙酸、马来酸、富马酸、苹果酸、柠檬酸、酒石酸、乳酸、苯甲酸、甲磺酸、乙磺酸、苯磺酸、甲苯磺酸、萘磺酸和萘二磺酸的盐;或者与常规碱的盐,诸如碱金属盐(例如钠盐和钾盐)、碱土金属盐(例如钙盐和镁盐)、来源于氨和有机胺(例如二乙胺、三乙胺、乙基二异丙基胺、普鲁卡因、二苄基胺、N-甲基吗啉、二氢松香胺(dihydroabiethylamine)、甲基哌啶、L-精氨酸、肌酸、胆碱、L-赖氨酸、乙二胺、N,N-二苄基乙二胺(benzathine)、乙醇胺、葡甲胺和氨丁三醇)的铵盐。
如本文中使用的,术语“前药”是指在展现其药理作用之前经历生物转化的化合物。前药可以使用众所周知的方法制备,诸如在Burgers药物化学和药物开发(1995)172-178,949-982(Manfred E.Wolff)中描述的那些。
如本文中使用的,术语“溶剂化物”是指与溶剂分子配位形成的配合物。当溶剂分子为水时,溶剂化物是水合物。
如本文所述的化合物可以被同位素标记,即,在其中的一个或多个原子被具有不同原子质量或质量数的原子替代。这样的同位素标记的化合物被认为在本发明的范围内。可以掺入化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素,诸如但不限于分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I和125I。
实施例
在下文中通过以下非限制性实施例示出本发明。
实施例1.采用CTG(CELLTITER-GLO)发光法测定化合物联用的细胞增殖抑制活性
测试原理:采用Promega公司的CellTiter-GloTM萤光素酶试剂盒,该方法使用萤光素酶作检测物,发光过程中萤光素酶需要ATP的参与,有代谢活性细胞的呼吸作用和其他生命活动过程可以产生ATP。向细胞培养基中加入等体积CellTiter-GloTM试剂,测量发光值,光信号与体系中ATP量成正比,ATP与活细胞数正相关,因此用于化合物对细胞增殖活性抑制的检测。为了检测不同作用机制的化合物联用后是否具有叠加或协同效果,设计本联用实验。
试验方法:按不同细胞要求配制完全培养基,复苏细胞(ATCC),传两代左右选择生长状态良好的细胞株,收集对数生长期细胞并计数,重悬细胞至合适浓度,将细胞悬液接种于384孔板,每孔加50μL细胞悬液,种板密度为600个细胞/孔,培养板放置于37℃、5% CO2培养箱中过夜。第二天将待测化合物用DMSO配制成储存液,以HPD 300e按照预定排布(9*9矩阵)加药;1000rpm离心1分钟后,37℃、5%二氧化碳培养箱中孵育72小时。加入25μL/孔的CellTiter Glo结束反应,室温避光孵育30分钟,轻轻震荡后在Envision进行检测。读取发光值,按照公式细胞生长抑制率%=(1-As/Ac)×100计算抑制率。其中As为样品(细胞+CTG+待测化合物),Ac为正常生长细胞对照(细胞+CTG+DMSO)。在EXCEL中输入每个浓度(X)对应的抑制率Inh%(Y),用XLfit插件根据内置四参数拟合公式Y=Bottom+(Top-Bottom)/(1+(IC50/X)*HillSlope)计算出每个化合物的半数抑制浓度IC50值。以SynergyFinder计算协同分数(Bliss)值,其中小于-10表明两种药物之间的相互作用是拮抗的,在-10到10之间表明两种药物之间的相互作用是相加的,大于10表明两种药物之间的相互作用是协同的。
结果表明,阿兹夫定(FNC,化合物1)和1-((1S,4S)-4-羟基环己基)-3-甲基-8-(6-(1-甲基-1H-吡唑-4-基)吡啶-3-基)-1H-咪唑并[4,5-c]喹啉-2(3H)-酮(化合物2)联合后,在多个测试细胞株上表现出协同效应。
体内抗肿瘤药效学评价
实验原理:首先建立肿瘤的实验动物模型,在成功建立肿瘤动物模型的基础上,对动物实验样品进行抗肿瘤治疗,最后通过观察治疗效果对药物的有效性、安全性以及作用特点做出正确的评价。
实施例2:化合物1联用化合物2在HCT-116人结肠癌模型上的药效评价
人结肠癌HCT116细胞体外单层培养,培养条件为McCoy’s 5a培养基中加10%胎牛血清和1%青霉素/链霉素/两性霉素B,于37℃、5% CO2孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80%-90%并且数量到达要求时,收取细胞。将0.1mL(5×106个)的HCT116细胞皮下接种于每只小鼠(BALB/c裸鼠,雌性,6-8周龄)的右后背近上肢侧,肿瘤平均体积达到约~125mm3时开始分组给药。每周测量2次肿瘤体积,实验结束时,计算肿瘤生长抑制率(TGI(%)=[1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100%)。
实验分组和给药方案:
1.溶媒对照组
2.化合物1,1mg/kg,PO(口服),QD(每天给药一次)
3.化合物2,20mg/kg,PO(口服),QD(每天给药一次)
4.化合物1+化合物2,1mg/kg+20mg/kg,PO(口服),QD(每天给药一次)
如图1所示,给药后第12天,溶媒对照组的肿瘤体积为787mm3,化合物1组的肿瘤体积为257mm3,TGI为80.0%,显著抑制了肿瘤生长;化合物2组的肿瘤体积为262mm3,TGI为79.3%,显著抑制了肿瘤生长;化合物1联合化合物2组的肿瘤体积为148mm3,TGI为96.5%,显示出显著的协同抑瘤作用。
结果表明,阿兹夫定(FNC,化合物1)和1-((1S,4S)-4-羟基环己基)-3-甲基-8-(6-(1-甲基-1H-吡唑-4-基)吡啶-3-基)-1H-咪唑并[4,5-c]喹啉-2(3H)-酮(化合物2)后,相对单药表现出更优的癌细胞(结肠癌)抑制作用。
实施例3:化合物1联用化合物2在MKN45人胃癌模型上的药效评价
人胃癌MKN45细胞体外单层培养,培养条件为RPMI 1640培养基中加10%胎牛血清和1%青霉素/链霉素/两性霉素B,于37℃、5%CO2孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80%-90%并且数量到达要求时,收取细胞。将0.1mL(5×106个)的MKN45细胞皮下接种于每只小鼠(BALB/c裸鼠,雌性,6-8周龄)的右后背近上肢侧,肿瘤平均体积达到约~150mm3时开始分组给药。每周测量2次肿瘤体积,实验结束时,计算肿瘤生长抑制率(TGI(%)=[1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100%)。
实验分组和给药方案:
1.溶媒对照组
2.化合物1,1mg/kg,PO(口服),QD(每天给药一次)
3.化合物2,10mg/kg,PO(口服),QD(每天给药一次)
4.化合物1+化合物2,1mg/kg+10mg/kg,PO(口服),QD(每天给药一次)
如图2所示,给药后第21天,溶媒对照组的肿瘤体积为965mm3,化合物1组的肿瘤体积为913mm3,TGI为6.3%,未见抑瘤作用;化合物2组的肿瘤体积为758mm3,TGI为25.2%,表现轻微抑制肿瘤生长的作用;化合物1联合化合物2组的肿瘤体积为454mm3,TGI为62.3%,显示出显著的协同抑瘤作用。
结果表明,阿兹夫定(FNC,化合物1)和1-((1S,4S)-4-羟基环己基)-3-甲基-8-(6-(1-甲基-1H-吡唑-4-基)吡啶-3-基)-1H-咪唑并[4,5-c]喹啉-2(3H)-酮(化合物2)后,相对单药表现出更优的癌细胞(胃癌)抑制作用。
Claims (12)
1.一种药物组合物,所述药物组合物包含:
(a)阿兹夫定或其药用盐、前药、水合物、溶剂化物或同位素标记的类似物
以及
(b)PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂或其药用盐、前药、水合物、溶剂化物或同位素标记的类似物。
2.根据权利要求1所述的药物组合物,其中所述药物组合物进一步包含免疫治疗剂,所述免疫治疗剂选自PD-1阻断剂或PD-L1阻断剂或CTLA-4阻断剂。
3.根据权利要求1所述的药物组合物,其中所述PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂选自PI3K抑制剂、ATR抑制剂、mTOR抑制剂,PI3K和mTOR双重抑制剂,PI3K和ATR双重抑制剂,ATR和mTOR双重抑制剂,以及PI3K、ATR和mTOR三重抑制剂。
4.根据权利要求1-3中任一项所述的药物组合物,其中所述PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂为ATR抑制剂,所述ATR抑制剂选自:VE-821、Berzosertib(VE-822,M6620,VX-970)、M4344(VX-803)、Ceralasertib(AZD6738)、M1774、ATRN-119、IMP9064、RP-3500、ART-0380、Elimusertib、AZD-1390、M-4076、XRD-0394。
5.根据权利要求1-3中任一项所述的药物组合物,其中所述PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂为mTOR抑制剂,所述mTOR抑制剂选自:依维莫司、雷帕霉素(西罗莫司)、MHY1485、Torin 1、AZD-8055、Dactolisib(BEZ235)、Sapanisertib(INK-128,MLN0128,TAK-228)、Temsirolimus(替西罗莫司)、Torin 2、Torkinib、Omipalisib(GSK2126458)、PI-103、Vistusertib(AZD2014)、PF-04691502、Samotolisib、GNE-493、PKI-179、PQR626、WYE-687、DS-7423、MHY-1685、GNE-477。
6.根据权利要求1-3中任一项所述的药物组合物,其中所述PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂为PI3K抑制剂,所述PI3K抑制剂选自:Aliqopa(Copanlisib)、BYL719、VS-5584、GSK2126458(Omipalisib)、GSK1059615、Bimiralisib(PQR309)、PQR530、BGT226(NVP-BGT226 maleate)、Apitolisib(GDC-0980;GNE390;RG7422)、GSK2636771、LAS195319、HMPL-689、Dactolisib(BEZ235)、Pictilisib(GDC-0941)、Eganelisib(IPI549)、Duvelisib(IPI-145)、Samotolisib(LY3023414)、Taselisib(GDC-0032)、PI-103、Copanlisib(BAY80-6946)、GDC-0077(RG6114)、Buparlisib(BKM120,NVP-BKM120)、PF-04691502、AZD8186、PKI-402、Voxtalisib(XL765)。
7.根据权利要1-3中任一项所述的药物组合物,其中所述PI3K抑制剂和/或ATR抑制剂和/或mTOR抑制剂为PI3K/mTOR抑制剂1-((1S,4S)-4-羟基环己基)-3-甲基-8-(6-(1-甲基-1H-吡唑-4-基)吡啶-3-基)-1H-咪唑并[4,5-c]喹啉-2(3H)-酮:
8.根据权利要求2所述的药物组合物,其中所述免疫治疗剂选自PD-1抗体或其抗原结合片段、PD-L1抗体或其抗原结合片段以及可溶性PD-1或CTLA-4抗体或其抗原结合片段。
9.根据权利要求1-3中任一项所述的药物组合物,其中所述药物组合物还包含另外的用于预防和/或治疗癌症或肿瘤的药物(诸如小分子、多肽、核酸、抗体、抗体偶联药物)。
10.根据权利要求1-9中任一项所述的药物组合物在制备用于预防和/或治疗癌症或肿瘤的药物中的用途。
11.根据权利要求10所述的用途,其中所述癌症和肿瘤包括:皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、胰腺癌、前列腺癌、肺癌、骨癌、脑癌、神经细胞瘤、直肠癌、结肠癌、家族性腺瘤性息肉性癌、遗传性非息肉性结直肠癌、食管癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、肾癌、肾实质癌、宫颈癌、子宫体癌、子宫内膜癌、绒毛膜癌、睾丸癌、泌尿癌、黑素瘤、脑肿瘤诸如成胶质细胞瘤、星形细胞瘤、脑膜瘤、成神经管细胞瘤和外周神经外胚层肿瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、白血病、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性骨髓性白血病(AML)、慢性粒细胞白血病(CML)、成人T细胞白血病淋巴瘤、弥漫性大B细胞淋巴瘤(DLBCL)、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、成视网膜细胞瘤、脉络膜黑素瘤、精原细胞瘤、横纹肌肉瘤、颅咽管瘤、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤和浆细胞瘤。
12.根据权利要求10所述的用途,其中所述癌症和肿瘤选自结肠癌、小细胞肺癌、胃癌和胰腺癌。
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