CN110382707A - 生物标志在鉴定将对用prmt5抑制剂治疗有响应的癌症患者中的用途 - Google Patents
生物标志在鉴定将对用prmt5抑制剂治疗有响应的癌症患者中的用途 Download PDFInfo
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- CN110382707A CN110382707A CN201880013998.5A CN201880013998A CN110382707A CN 110382707 A CN110382707 A CN 110382707A CN 201880013998 A CN201880013998 A CN 201880013998A CN 110382707 A CN110382707 A CN 110382707A
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Abstract
本发明涉及一种鉴定患者的方法,所述患者可能对用蛋白质精氨酸N‑甲基转移酶5(PRMT5)抑制剂治疗有响应,所述方法包括:评估来自所述患者的生物学样品中是否存在剪接体改变,其中任何所述改变的存在指示相比不存在任何所述突变或改变,所述患者对用所述PRMT5抑制剂治疗有响应的可能性更高。
Description
技术领域
本文提供了鉴定患者的方法和治疗所述患者的方法,所述患者对用蛋白质精氨酸N-甲基转移酶5抑制剂治疗有响应的可能性高。
背景技术
蛋白质精氨酸N-甲基转移酶5(PRMT5),也被描述为Hsl7、Jbp1、Skb1、Capsuleen或Dart5,是负责精氨酸的单二甲基化作用和对称二甲基化作用的主要甲基转移酶之一。PRMT5属于Sym Arg二甲基转移酶家族。催化活性与致癌肺驱动途径激活(剪接和WNT信号传导)以及肿瘤抑制因子和肿瘤免疫原性趋化因子的表观遗传抑制相关联。蛋白质水平和定位与较高的细胞甲基化、支气管上皮表型的丧失和不良的疾病进展相关。
组蛋白和非组蛋白上的翻译后精氨酸甲基化对于多种生物学过程是至关重要的,例如基因组组织、转录、分化、剪接体功能、信号转导和细胞周期进程的调控、干细胞和T细胞命运。后生动物的PRMT5与也称为Wdr77的甲基转移酶复合体蛋白50(MEP50)、雄激素受体辅激活物p44和Valois形成功能性复合体。升高的PRMT5-MEP50蛋白质水平和细胞质累积两者均与癌症肿瘤发生有关,并在最近才与不良的临床结果相关。除综合性酶学研究之外,解决PRMT5-MEP50复合体的催化功能和支架功能两者的细胞拯救实验证实了蛋白质水平、定位和酶功能之间的致癌联系。这种相关性使PRMT5成为针对癌症和其他疾病的必需小分子药物靶标。
PRMT5是II型PRMT亚家族的成员,该亚家族使用S-腺苷基甲硫氨酸(SAM)在组蛋白和非组蛋白底物上产生对称二甲基化的精氨酸、和S-腺苷基高半胱氨酸(SAH)。PRMT5活性的调节通过大量不同的结合配偶体、翻译后修饰、miRNA和亚细胞定位发生。Arg3上的组蛋白H2A和H4以及Arg8上的组蛋白H3的甲基化调节染色质组织,以特异性抑制/激活参与分化、转化、细胞周期进展和肿瘤抑制的基因转录物。此外,PRMT5介导的Arg3上组蛋白H4的甲基化可能募集DNA甲基转移酶DNMT3A以偶联组蛋白和DNA甲基化以进行长期基因沉默。
非组蛋白甲基化可以在细胞质或细胞核中发生,这取决于PRMT5的细胞定位。核剪接体组装所需的Sm蛋白D1和D3的甲基化作为含有“甲基转移酶复合体”的PRMT5的一部分发生在细胞质中。通过小鼠神经干细胞中的条件性PRMT5敲除提供了PRMT5参与剪接的进一步证据。缺乏PRMT5的细胞显示内含子的选择性保留和具有弱5’供体位点的外显子的跳跃。除了在剪接中的作用外,PRMT5通过直接甲基化关键信号结节如p53、30EGFR、26CRAF、3PI3K/AKT、64和NFkB影响参与细胞命运和体内平衡的关键途径。
由于PRMT5是主要的sym-Arg甲基转移酶之一并且涉及多种细胞过程,因此增加的蛋白质表达似乎是其致肿瘤性的重要因素。有趣的是,PRMT5在套细胞淋巴瘤(MCL)中的翻译似乎受到miRNA的调节。尽管与正常B淋巴细胞相比,MCL细胞显示较少的mRNA和较慢的PRMT5转录率,但是PRMT5水平以及H3R8和H4R3的甲基化显著增加。结合PRMT5的3’UTR区域的miRNA的重新表达降低了PRMT5蛋白质水平。引人注目的是,在人PRMT5基因中发现PRMT5反义RNA,这支持了特定翻译调控的假设,而不是高mRNA表达水平。
尽管PRMT5被高度认为是临床相关靶标,但是到目前为止只有非常少的选择性PRMT5抑制剂被公开。最近,一种在多种MCL异种移植模型中具有抗肿瘤活性的新颖的亚纳摩尔有效PRMT5抑制剂(EPZ015666),已被描述为适用于进一步验证PRMT5在癌症中的生物学和作用的首个化学探针(Chan-Penebre E,Kuplast KG,Majer CR等人A selectiveinhibitor of PRMT5with in vivo and in vitro potency in MCL models.[PRMT5的选择性抑制剂在MCL模型中具有体内和体外效力]Nat Chem Biol.[自然化学生物学]2015年6月;11(6):432-437)。
WO 2014100695 A1披露了可以用于抑制PRMT5活性的化合物;还描述了使用所述化合物用于治疗PRMT5介导的障碍的方法。
WO 2014100730 A1披露了含有二氢或四氢异喹啉的PRMT5抑制剂及其用途。
Devkota,K.等人(ACS Med Chem Lett[ACS药物化学快报],2014.5:第293页-第297页)描述了天然产物西奈芬净的一系列类似物的合成和这些类似物抑制EHMT1和EHMT2的能力。
WO 2003070739披露了A1腺苷受体的部分和完全激动剂,它们的制备和它们的治疗用途。
WO 2012082436披露了作为组蛋白甲基转移酶调节剂的化合物和组合物,以及用于治疗受组蛋白甲基转移酶活性调节影响的疾病的化合物和组合物。
WO 2014100719披露了PRMT5抑制剂及其用途。
WO 03074083披露了选择性杀死甲硫腺苷磷酸化酶缺乏的细胞的组合疗法。MTA的类似物在本文描述为抗毒剂。
Kung,P.-P.等人(Bioorg Med Chem.Lett[生物学有机和药物化学快报],2005.15:第2829页-第2833页)描述了新颖的人5’-脱氧-5’-甲硫腺苷磷酸化酶(MTAP)底物的设计、合成和生物学评价。
WO 2012075500披露了组蛋白甲基转移酶的7-脱氮嘌呤调节剂。
WO2014035140披露了用于调节组蛋白甲基转移酶活性的化合物和组合物。
WO 2015200680描述了PRMT5抑制剂及其用途。
WO 2017/032840和WO 2017/153186还描述了PRMT5抑制剂及其用途,并且通过引用并入本文。
PRMT5通过多种机制与肺癌相关联。NSCLC中升高的PRMT5和MEP50表达与较差的存活高度相关。通过其中PRMT5的高细胞质表达与不良预后直接相关(可能通过上皮-间充质转化和组蛋白甲基化而介导)的研究显示了对肺腺癌中这种升高的表达的机械学深刻理解。此外,PRMT5过表达导致裸鼠体内肿瘤的形成。PRMT5的细胞转化能力背后的机制尚不清楚,但酶被假定在细胞死亡、细胞周期进展、剪接、细胞生长和增殖中起作用。
临床前数据表明,PRMT5抑制导致肺癌群体的一个亚组中肺癌细胞死亡,而不同的亚组不受长期暴露于PRMT5抑制剂的影响。因此,显然需要药效学(PD)和/或预测性生物标志,以确定特定患者的PRMT5介导的疾病是否具有对用PRMT5抑制剂治疗有响应的高可能性,或测量用PRMT5抑制剂治疗患有NSCLC或SCLC或PRMT5介导的其他疾病的患者的药效学作用。目前还没有此类生物标志。
发明内容
本文披露了鉴定患者的方法,所述患者将对用蛋白质精氨酸N-甲基转移酶5(PRMT5)抑制剂治疗有响应的可能性高。
PRMT5抑制剂可以结合至PRMT5酶,与天然底物SAM(S-腺苷基-L-甲硫氨酸)相竞争,以抑制这种酶。
因此预期PRMT5抑制剂及其药物组合物可以用于治疗或预防,特别是用于治疗以下疾病,如血液障碍、代谢障碍、自身免疫障碍、癌症、炎性疾病、心血管疾病、神经退行性疾病、胰腺炎、多器官衰竭、肾病、血小板聚集、精子活动力、移植排斥、移植物排斥、肺损伤等。
特别地,PRMT5抑制剂或其药物组合物可以用于治疗或预防,特别是用于治疗以下疾病,如过敏症、哮喘、造血系统癌、肺癌、前列腺癌、黑色素瘤、代谢障碍、糖尿病、肥胖症、血液障碍、镰状细胞贫血等。
PRMT5抑制剂或其药物组合物可以用于治疗或预防,特别是用于治疗以下疾病,例如增生性障碍,如自身免疫性疾病、癌症、良性赘生物或炎性疾病。
PRMT5抑制剂或其药物组合物可以用于治疗或预防,特别是用于治疗以下疾病,如代谢障碍,包括糖尿病、肥胖症;增生性障碍,包括癌症、造血系统癌、肺癌、前列腺癌、黑色素瘤或胰腺癌;血液障碍;血红蛋白病;镰状细胞贫血;β-地中海贫血、炎性疾病、以及自身免疫性疾病,例如风湿性关节炎、系统性红斑狼疮、斯耶格伦氏综合征(Sjogren’ssyndrome)、腹泻、胃食管反流疾病等。
在一些实施例中,PRMT5的抑制可以用于治疗或预防,特别是用于治疗以下非限制性列表的癌症:乳腺癌、肺癌、食道癌、膀胱癌、造血系统癌、淋巴瘤、成神经管细胞瘤、直肠腺癌、结肠腺癌、胃癌、胰腺癌、肝癌、腺样囊性癌、肺腺癌、头颈部鳞状细胞癌、脑癌、肝细胞癌、肾细胞癌、黑色素瘤、少突神经胶质瘤、卵巢透明细胞癌以及卵巢浆液性囊腺癌。
可以被治疗或预防,特别是治疗的代谢障碍的实例包括但不限于糖尿病或肥胖症。
可以被治疗或预防,特别是治疗的血液障碍的实例包括但不限于血红蛋白病,如镰状细胞疾病或β-地中海贫血。
可以被治疗或预防,特别是治疗的癌症的实例包括但不限于听神经瘤、腺癌、肾上腺癌、肛门癌、血管肉瘤(例如,淋巴管肉瘤、淋巴管内皮肉瘤、血管肉瘤)、阑尾癌、良性单克隆免疫球蛋白病、胆管癌(例如,肝胆管型肝癌)、膀胱癌、乳腺癌(例如,乳腺腺癌、乳腺乳头状癌、乳腺癌、乳腺髓样癌)、脑癌(例如,脑膜瘤;神经胶质瘤,例如星形细胞瘤、少突神经胶质瘤;成神经管细胞瘤)、支气管癌、类癌瘤、子宫颈癌(例如,子宫腺癌)、脊索瘤、绒毛膜癌、颅咽管瘤、结肠直肠癌(例如,结肠癌、直肠癌、结肠直肠腺癌)、上皮癌、室管膜瘤、内皮肉瘤(例如,卡波西肉瘤、多发性特发性出血性肉瘤)、子宫内膜癌(例如,子宫癌、子宫肉瘤)、食道癌(例如,食管腺癌、巴雷特氏腺癌(Barrett’s adenocarinoma))、尤文氏肉瘤(Ewingsarcoma)、眼癌(例如,眼内黑色素瘤、成视网膜细胞瘤)、常见嗜酸性粒细胞增多症、胆囊癌、胃癌(例如,胃腺癌)、胃肠道基质肿瘤(GIST)、头颈部癌(例如,头颈部鳞状细胞癌、口腔癌(例如,口腔鳞状细胞癌(OSCC))、喉癌(例如,咽癌、喉癌、鼻咽癌、口咽癌))、造血系统癌症(例如,白血病如急性淋巴细胞性白血病(ALL)(例如,B细胞ALL、T细胞ALL)、急性髓细胞性白血病(AML)(例如,B细胞AML、T细胞AML)、慢性髓细胞性白血病(CML)(例如,B细胞CML、T细胞CML)、以及慢性淋巴细胞性白血病(CLL)(例如,B细胞CLL、T细胞CLL);淋巴瘤如何杰金淋巴瘤(HL)(例如,B细胞HL、T细胞HL)以及非何杰金淋巴瘤(NHL)(例如,B细胞NHL如弥散性大细胞淋巴瘤(DLCL)(例如,弥散性大B细胞淋巴瘤(DLBCL))、滤泡性淋巴瘤、慢性淋巴细胞性白血病/小淋巴细胞性淋巴瘤(CLL/SLL)、套细胞淋巴瘤(MCL)、边缘区B细胞淋巴瘤(例如,粘膜相关淋巴组织(MALT)淋巴瘤、淋巴结边缘区B细胞淋巴瘤、脾边缘区B细胞淋巴瘤)、原发性纵隔B细胞淋巴瘤、伯基特淋巴瘤(Burkitt lymphoma)、淋巴质浆细胞淋巴瘤(即,“沃尔丹斯特伦氏巨球蛋白血症(Waldenstrom’s macro globulinemia)”)、免疫母细胞大细胞淋巴瘤、毛细胞白血病(HCL)、前体B成淋巴细胞性淋巴瘤以及原发性中枢神经系统(CNS)淋巴瘤;以及T细胞NHL如前体T成淋巴细胞性淋巴瘤/白血病、外周T细胞淋巴瘤(PTCL)(例如,皮肤T细胞淋巴瘤(CTCL)(例如,毒蕈样霉菌病、西泽里综合征(Sezarysyndrome))、血管免疫母细胞性T细胞淋巴瘤、结外自然杀伤T细胞淋巴瘤、肠病型T细胞淋巴瘤、皮下脂膜炎样T细胞淋巴瘤、间变性大细胞淋巴瘤);如上所描述的一种或多种白血病/淋巴瘤的混合;以及多发性骨髓瘤(MM))、重链病(例如,α链病、γ链病、μ链病)、成血管细胞瘤、炎性肌纤维母细胞肿瘤、免疫细胞淀粉样变性、肾癌(例如,肾母细胞瘤,又称维尔姆斯氏肿瘤(Wilms’tumor)、肾细胞癌)、肺癌(例如,肝细胞癌(HCC)、恶性肝细胞瘤)、肺癌(例如,支气管癌、非小细胞肺癌(NSCLC)、鳞状肺癌(SLC)、肺腺癌、Lewis肺癌、肺神经内分泌肿瘤:典型类癌、非典型类癌、小细胞肺癌(SCLC)、以及大细胞神经内分泌癌)、平滑肌肉瘤(LMS)、肥大细胞增多症(例如,系统性肥大细胞增多症)、骨髓增生异常综合征(MDS)、间皮瘤、骨髓增生性障碍(MPD)(例如,真性红细胞增多症(PV)、特发性血小板增多症(ET)、原因不明的骨髓化生(AMM)又称骨髓纤维化(MF)、慢性特发性骨髓纤维化、慢性髓细胞性白血病(CML)、慢性嗜中性粒细胞白血病(CNL)、高嗜酸性粒细胞综合征(HES))、成神经细胞瘤、神经纤维瘤(例如,神经纤维瘤病(NF)1型或2型、神经鞘瘤病)、神经内分泌癌(例如,胃肠胰腺神经内分泌肿瘤(GEP-NET)、类癌肿瘤)、骨肉瘤、卵巢癌(例如,囊腺癌、卵巢胚胎癌、卵巢腺癌)、乳头状腺癌、胰腺癌(例如,胰腺腺癌、导管内乳头状粘液肿瘤(IPMN)、胰岛细胞瘤)、阴茎癌(例如,阴茎和阴囊的佩吉特氏病(Paget’s disease))、松果体瘤、原神经外胚层肿瘤(PNT)、前列腺癌(例如,前列腺腺癌)、直肠癌、横纹肌肉瘤、唾液腺癌、皮肤癌(例如,鳞状细胞癌(SCC)、角化棘皮瘤(KA)、黑色素瘤、基底细胞癌(BCC))、小肠癌(例如,阑尾癌)、软组织肉瘤(例如、恶性纤维组织细胞瘤(MFH)、脂肪肉瘤、恶性周围神经鞘瘤(MPNST)、软骨肉瘤、纤维肉瘤、粘液肉瘤)、皮脂腺癌、汗腺癌、滑膜瘤、睾丸癌(例如,精原细胞瘤、睾丸胚胎癌)、甲状腺癌(例如,甲状腺乳头状癌、乳头状甲状腺癌(PTC)、甲状腺髓样癌)、尿道癌、阴道癌、以及外阴癌(例如,外阴的佩吉特氏病)。
可以被治疗或预防,特别是治疗的神经退行性疾病的实例包括但不限于运动神经元疾病、进行性核上性麻痹、皮质基底节变性、皮克氏病、阿耳茨海默病、AIDS相关的痴呆、帕金森氏病、肌萎缩性侧索硬化症、色素性视网膜炎、脊髓性肌萎缩症和小脑变性。
可以被治疗或预防,特别是治疗的心血管疾病的实例包括但不限于心脏肥大、再狭窄、动脉粥样硬化和肾小球性肾炎。
可以被治疗或预防,特别是治疗的炎性疾病的实例包括但不限于与以下相关的炎症:痤疮、贫血(例如,再生障碍性贫血、溶血性自身免疫性贫血)、鼻炎、哮喘、动脉炎(例如,多动脉炎、颞动脉炎、结节性动脉周围炎、高安氏动脉炎(Takayasu’s arteritis))、关节炎(例如,结晶性关节炎、骨关节炎、牛皮癣性关节炎、痛风性关节炎、反应性关节炎、类风湿性关节炎以及莱特氏关节炎(Reiter’s arthritis))、上呼吸道疾病、强直性脊柱炎、淀粉样变性、肌萎缩性侧索硬化、自身免疫性疾病、过敏症或过敏性反应、动脉粥样硬化、支气管炎、粘液囊炎、慢性前列腺炎、结膜炎、恰加斯病(Chagas disease)、慢性阻塞性肺病、憩室炎、皮肌炎(cermatomyositis)、糖尿病(例如,I型糖尿病、2型糖尿病)、皮肤病症(例如,牛皮癣、湿疹、湿疹超敏性反应、烧伤、皮炎、瘙痒(发痒))、子宫内膜异位、吉兰-巴雷综合征(Guillain-Barre syndrome)、感染、缺血性心脏病、川崎氏病(Kawasaki disease)、肾小球肾炎、牙龈炎、超敏反应、头痛(例如,偏头痛、紧张性头痛)、肠梗阻(例如,术后肠梗阻和脓毒症期间的肠梗阻)、特发性血小板减少性紫癜、间质性膀胱炎(疼痛性膀胱综合征)、胃肠道障碍(例如,选自消化性溃疡、局限性肠炎、憩室炎、胃肠道出血、嗜酸性胃肠道障碍(例如,嗜酸性食道炎、嗜酸性胃炎、嗜酸性胃肠炎、嗜酸性结肠炎)、胃炎、腹泻、胃食管返流疾病(GORD或其同义词GERD)、炎性肠病(IBD)(例如,克罗恩氏病(Crohn’s disease)、溃疡性结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、局部缺血性结肠炎、改道性结肠炎(diversioncolitis)、白塞氏综合征(Behcet’s syndrome)、未确定型结肠炎)以及炎性肠综合征(IBS))、狼疮、硬斑病、重症肌无力、心肌缺血、多发性硬化、肾病综合征、寻常天疱疮、恶性贫血(pemicious aneaemia)、消化性溃疡、多肌炎、原发性胆汁性肝硬变、与脑障碍相关的神经炎症(例如,帕金森氏病、亨廷顿舞蹈病(Huntington’s disease)以及阿耳茨海默病(Alzheimer’s disease))、前列腺炎、与颅放射性损伤相关的慢性炎症、盆腔炎性疾病、再灌注损伤、局限性肠炎、风湿热、系统性红斑狼疮、硬皮病、硬化症(scierodoma)、结节病、脊柱关节病、斯耶格伦氏综合征、甲状腺炎、移植排斥、腱炎、外伤或损伤(例如,冻疮、化学刺激物、毒素、疤痕、烧伤、身体损伤)、血管炎、白癜风以及韦格纳氏肉芽肿病(Wegener’sgranulomatosis)。
特别地,炎性疾病可以是急性炎性疾病(例如,由感染引起的炎症)。特别地,炎性疾病可以是慢性炎性疾病(例如,由哮喘、关节炎和炎性肠病引起的病症)。PRMT5抑制剂还可以用于治疗与外伤和非炎性肌痛相关的炎症。所述化合物还可以用于治疗与癌症相关的炎症。
可以被治疗或预防,特别是治疗的自身免疫性疾病包括但不限于关节炎(包括类风湿性关节炎、脊柱关节病、痛风性关节炎、退行性关节疾病如骨关节炎、系统性红斑狼疮、斯耶格伦氏综合征、强直性脊柱炎、未分化脊柱炎、白塞氏病、溶血性自身免疫性贫血、肌萎缩性侧索硬化、淀粉样变性、多发性硬化、急性痛肩、牛皮癣性和青少年性关节炎)、哮喘、动脉粥样硬化、骨质疏松症、支气管炎、腱炎、粘液囊炎、皮肤病症(例如,牛皮癣、湿疹、湿疹过敏性反应、烧伤、皮炎、瘙痒(发痒))、遗尿、嗜酸细胞性疾病、胃肠道障碍(例如,选自消化性溃疡、局限性肠炎、憩室炎、胃肠道出血、嗜酸性胃肠道障碍(例如,嗜酸性食道炎、嗜酸性胃炎、嗜酸性胃肠炎、嗜酸性结肠炎)、胃炎、腹泻、胃食管返流疾病(GORD或其同义词GERD)、炎性肠病(IBD)(例如,克罗恩氏病、溃疡性结肠炎、胶原性结肠炎、淋巴细胞性结肠炎、局部缺血性结肠炎、改道性结肠炎、白塞氏综合征、未确定型结肠炎)和炎性肠综合征(IBS))以及通过胃动力促进剂改善的障碍(例如,肠梗阻、术后肠梗阻和脓毒症期间的肠梗阻;胃食管返流疾病(GORD或其同义词GERD);嗜酸性食道炎、胃轻瘫如糖尿病胃轻瘫;食物不耐症和食物过敏症以及其他机能性肠障碍,如非溃疡性消化不良(NUD)和非心源性胸痛(NCCP,包括肋-软骨炎))。
在一个特别的实施例中,PRMT5抑制剂可以用于体细胞重编程,如将体细胞重编程为干细胞。在一个特别的实施例中,PRMT5抑制剂可以用于生殖细胞发育,并且因此设想用于生殖技术和再生医学领域。
其他可以被治疗或预防,特别是治疗的疾病包括但不限于缺血性损伤相关性心肌梗塞、免疫性疾病、中风、心律失常、毒素诱发性或酒精相关性肝病、阿司匹林敏感的鼻窦炎、囊性纤维化、癌痛和血液病,例如慢性贫血和再生障碍性贫血。
因此,本发明包括鉴定患者的方法,所述患者可能对用蛋白质精氨酸N-甲基转移酶5(PRMT5)抑制剂治疗有响应,所述方法包括:评估来自所述患者的生物学样品中是否存在以下任一种:
·PIC3CA激活突变,
·剪接体改变,
·细胞周期蛋白D1途径扩增,和/或
·WNT途径改变
其中任何所述突变或改变的存在指示相比不存在任何所述突变或改变,所述患者对用所述PRMT5抑制剂治疗有响应的可能性更高。
在优选的实施例中,所述剪接体改变包含选自由以下组成的组的基因中的突变:U2AF1、RBM10和KIAA1429。在一个具体实施例中,所述基因是U2AF1,并且所述突变是S34F。在另一个具体实施例中,基因是RBM10,并且突变选自由以下组成的组:I696fs、I348N和G840fs。在又另一个具体实施例中,基因是KIAA1429,并且突变选自由以下组成的组:L837V、F1260L、D251if、T1333M、V1548L、G397A和Q962E。其他剪接体改变还可以指示患者对用PRMT5抑制剂治疗有响应的可能性更高。
在另一个实施例中,PIC3CA激活突变选自由以下组成的组:H1047R、PG106-R108del、T1025A和E542K。然而,其他激活突变还可以指示患者对用PRMT5抑制剂治疗有响应的可能性更高。
在另一个实施例中,细胞周期蛋白D1途径扩增是细胞周期蛋白D1、CDK4或CDK6表达的扩增。然而,其他细胞周期蛋白D1途径扩增还可以指示患者对用PRMT5抑制剂治疗有响应的可能性更高。
在另一个实施例中,WNT途径改变包括自分泌WNT信号传导。优选地,WNT途径改变包括APC或CTNNB1基因中的突变。在一个具体实施例中,基因是APC,并且突变选自由以下组成的组:R213Q、R2673G、I1177M和D2796G。在另一个具体实施例中,基因是CTNNB1,并且突变选自由以下组成的组:Y670*、S45F和T41A。然而,其他WNT途径改变还可以指示患者对用PRMT5抑制剂治疗有响应的可能性更高。
在一个特别的实施例中,根据本发明的突变或改变包括剪接体改变,并且患者患有NSCLC。
在另一个特别的实施例中,根据本发明的突变或改变包括细胞周期蛋白D1途径扩增或WNT途径改变,并且患者患有NSCLC。
在另一个特别的实施例中,根据本发明的突变或改变包括PIC3CA激活突变,并且患者具有SCLC。
在本发明的一个优选的实施例中,PRMT5抑制剂是化合物2或化合物80。
本申请披露了SCLC中对PI3K-α激活突变的敏感性关联,以及NSCLC中对剪接体改变和WNT途径上调的敏感性关联。细胞周期蛋白D1途径扩增与NSCLC中PRMT5抑制剂响应相关。
本文进一步提供了用于鉴定如上所描述的生物学样品中一种或多种突变或改变的存在的试剂盒和引物。
通过参考以下结合附图进行的详细说明(形成本披露的一部分),可以更容易地理解所披露的方法、试剂盒和引物。应理解,所披露的方法、试剂盒和引物不限于本文所描述和/或显示的具体方法、试剂盒和引物,并且本文所使用的术语仅仅是出于通过举例来描述特别实施例的目的并且不旨在限制所要求保护的方法、试剂盒和引物。
除非上下文另有明确规定,否则对具体数值的引用至少包括所述具体值。当表达值的范围时,另一个实施例包括从一个具体值和/或至另一个具体值。此外,对范围中所叙述的值的引用包括所述范围内的每个值。所有范围都是包含性的和可组合的。
应理解,为了清楚起见,在单独的实施例的上下文中描述的所披露的方法、试剂盒和引物的某些特征也可以在单个实施例中组合提供。相反,为了简洁起见,在单个实施例的上下文中描述的所披露的方法、试剂盒和引物的不同特征也可以单独提供或以任何亚组合提供。
如本文所使用的,单数形式“一种”、“一个”和“所述”包括复数形式。
如本文所使用的,“治疗”和类似术语是指减轻癌症症状的严重程度和/或频率、消除癌症症状和/或所述症状的根本病因、减轻癌症症状和/或其根本病因的频率或可能性、以及改善或修复癌症直接或间接造成的损害。
“生物学样品”是指来自患者(其中可以获得癌细胞并且可以分离RNA)的任何样品。合适的生物学样品包括但不限于血液、淋巴液、骨髓、实体瘤样品或其任何组合。
如本文所使用的,“预扩增”是指在扩增步骤之前进行的PCR程序,以增加扩增步骤的模板cDNA的量。例如,可以使用PreAmp Master Mix(生命科技公司/应用生物系统公司(Life Technologies/Applied Biosystems)产品号4391128)进行预扩增步骤。
如本文所使用的,“扩增(amplifying,amplify)”和类似术语是指产生核酸样品的许多相同拷贝。用于扩增核酸样品的合适技术包括但不限于聚合酶链反应(PCR)和实时聚合酶链反应(RT-PCR)。在一些实施例中,扩增步骤包括RT-PCR。
“新一代测序”或“NGS”是指以高通量平行方式(例如,可以同时测序大于103、104、105或更多的分子)确定单个核酸分子的核苷酸序列(例如,在单分子测序中)或克隆扩增的单个核酸分子的代替物的任何测序方法。示例性的新一代测序技术包括通过合成测序、通过连接测序和通过杂交测序。示例性的新一代测序方法包括大规模平行签名测序(Massively Parallel Signature Sequencing)(林克斯治疗公司(Lynx Therapeutics));454焦磷酸测序(pyro-sequencing)(454生命科学公司/罗氏诊断公司(Life Sciences/Roche Diagnostics));固相、可逆染料-终止子测序(索莱克斯公司/依诺米那公司(Solexa/Illumina));SOLiD技术(应用生物系统公司(Applied Biosystems));离子半导体测序(离子激流公司(Ion Torrent));和DNA纳米球测序(全基因组学公司(CompleteGenomics))。某些NGS平台的说明可在以下中找到:Shendure等人,“Next-generation DNAsequencing[新一代测序],”Nature[自然],2008,第26卷,第10期,1135-1145;
NGS平台
在一些实施例中,高通量、大规模平行测序采用使用可逆染料终止子进行通过合成测序。在其他实施例中,经由通过连接测序进行测序。在其他实施例中,测序是单分子测序。新一代测序技术的实例包括但不限于焦磷酸测序、可逆染料终止子测序、SOLiD测序、离子半导体测序、Helioscope单分子测序等。
Ion TorrentTM(加利福尼亚州卡尔斯巴德的生命科技公司)扩增子测序系统采用基于流的方式,检测在DNA复制中并入未修饰的核苷酸期间由氢离子释放引起的pH变化。为了与该系统一起使用,测序文库最初通过生成侧接测序接头的DNA片段而产生。在一些实施例中,可通过乳液PCR在颗粒上克隆扩增这些片段。然后将具有扩增模板的颗粒置于硅半导体测序芯片中。在复制期间,芯片被一个接一个地核苷酸淹没,并且如果核苷酸与芯片的特定微孔中的DNA分子互补,则将所述核酸并入。当核苷酸通过DNA分子中的聚合酶并入时,质子自然释放,导致可检测的pH局部变化。然后溶液的pH在该孔中发生变化并通过离子传感器检测。如果模板序列中存在均聚物重复,则将在单个周期中并入多个核苷酸。这导致相应数量的释放的氢和按比例地更高的电子信号。
454TM GS FLXTM测序系统(德国罗氏公司(Roche))在大规模平行焦磷酸测序系统中采用了基于光的检测方法。焦磷酸测序使用DNA聚合,一次添加一个核苷酸种类,并检测和量化通过释放附着的焦磷酸盐所发出的光而添加到给定位置的核苷酸数量。为了与454TM系统一起使用,将接头连接的DNA片段固定在油包水乳液中的小DNA捕获珠上,并通过PCR(乳液PCR)扩增。将每个DNA结合的珠置于皮可滴定板(picotiter plate)上的孔中,并将测序试剂递送穿过板的孔。在测序运行期间,将四个DNA核苷酸以固定顺序依次添加在整个皮可滴定板装置上。在核苷酸流动期间,平行测序结合到每个珠上的数百万拷贝的DNA。当将与模板链互补的核苷酸添加到孔中时,将核苷酸并入到现有的DNA链上,产生由仪器中的CCD照相机记录的光信号。
基于可逆染料终止子的测序技术:首先将DNA分子附着至载玻片上的引物上并扩增,从而形成局部克隆集落。添加四种类型的可逆终止子碱基(RT-碱基),并洗去未并入的核苷酸。与焦磷酸测序不同,DNA一次只能延伸一个核苷酸。照相机拍摄荧光标记的核苷酸图像,然后将染料与末端3’阻断剂一起从DNA中化学除去,从而允许下一个周期。
Helicos的单分子测序使用添加到polyA尾接头的DNA片段,其附着在流动细胞表面。在每个周期中,添加DNA聚合酶和单种荧光标记的核苷酸,导致表面固定的引物-模板双链体的模板依赖性延伸。读数由Helioscope测序仪执行。采集平铺整个阵列的图像后,荧光标签的化学切割和释放允许随后的延伸和成像周期。
像“老式”染料-终止电泳测序一样,合成测序(SBS)依靠DNA聚合酶并入核苷酸来确定碱基序列。将具有固定接头的DNA文库变性为单链并嫁接到流动细胞中,然后进行桥式扩增以在玻璃芯片上形成高密度斑点阵列。可逆终止子方法使用染料终止子的可逆形式,每次添加一个核苷酸,通过重复除去封闭基团以检测每个位置的荧光以允许另一个核苷酸的聚合。核苷酸并入的信号可以随荧光标记的核苷酸、磷酸盐驱动的光反应和氢离子传感全部被使用而变化。SBS平台的实例包括Illumina GA和HiSeq 2000。个人测序系统(依诺米那公司(Illumina,Inc.))还采用使用可逆终止子化学的合成测序。
与通过合成方法测序相反,通过连接方法测序使用DNA连接酶来确定靶序列。该测序方法依赖于在模板DNA链上通过局部互补性将相邻的寡核苷酸酶促连接。该技术使用了所有可能的具有固定长度、根据测序位置进行标记的寡核苷酸的分区。对寡核苷酸进行退火并连接,并且通过DNA连接酶对匹配序列的优先连接导致在该位置的二核苷酸编码的色空间信号(通过释放沿着寡核苷酸对应已知位置处的已知核苷酸的荧光标记的探针)。该方法主要由生命科技公司的SOLiDTM测序仪使用。在测序之前,通过乳液PCR扩增DNA。将每个仅含有相同DNA分子拷贝的所得珠沉积在固体平面底物上。
SMRTTM测序是基于通过合成方式的测序。DNA在零模式波导(ZMW)-小孔状容器中合成,其中捕获工具位于孔底部。使用未修饰的聚合酶(附着于ZMW底部)和在溶液中自由流动的荧光标记的核苷酸进行测序。以这样的方式构建孔,即仅检测在孔底部发生的荧光。将荧光标记与其并入DNA链的核苷酸分离,留下未修饰的DNA链。
用于扩增突变体的引物
本领域技术人员知道核酸的扩增需要与核酸链的5’和3’区域(位于待扩增区域的侧翼)互补并结合的引物。如本文所使用的,“引物对”是指在扩增步骤中使用的正向引物和反向引物。
本领域技术人员可以使用已知方法鉴定适合用于扩增和检测如上所描述的特定突变的引物。
基因组学和分析
功能基因组学和转录分析可以用于使用标准技术和方案分析途径和基因的扩增。
用于在所披露的方法中使用的PRMT5抑制剂
本文提供了适合用于在所披露的方法中使用的PRMT5抑制剂。在一些实施例中,如果样品中存在一种或多种突变或扩增(包括PIC3CA激活突变、剪接体改变、细胞周期蛋白D1途径扩增和/或WNT途径改变),则可以用PCT/EP2016/070097(通过引用并入本文)披露的PRMT5抑制剂(包括其任何互变异构或立体化学异构形式、及其N-氧化物、其药学上可接受的盐或其溶剂化物(合适的R基团也披露于PCT/EP2016/070097中))治疗患者。例如,在一些方面,可以用化合物2或化合物80(包括其任何互变异构或立体化学异构形式、及其N-氧化物、其药学上可接受的盐或其溶剂化物)治疗患者。在一些方面,药学上可接受的盐是HCl盐。
在一些实施例中,如果样品中存在一种或多种突变或扩增(包括PIC3CA激活突变、剪接体改变、细胞周期蛋白D1途径扩增和/或WNT途径改变),则可以用PRMT5抑制剂治疗患者,其中所述PRMT5抑制剂是抗PRMT5抗体。
可以通过常规化学方法(如在Pharmaceutical Salts:Properties,Selection,and Use[药用盐:特性、选择及用途],P.Heinrich Stahl(编辑),Camille G.Wermuth(编辑),ISBN:3-90639-026-8,硬封面,388页,2002年8月(通过引用并入本文)中所描述的方法)从含有碱性或酸性部分的母体化合物合成盐。总体上,此类盐可以通过在水中或在有机溶剂中,或在两者的混合物中,将这些化合物的游离酸或碱形式与适当的碱或酸进行反应来制备;总体上,使用非水性介质例如乙醚、乙酸乙酯、乙醇、异丙醇、或乙腈。用于在所披露的方法中使用的PRMT5抑制剂可以作为单盐或二盐存在,这取决于形成所述盐的酸的pKa。
酸加成盐可用多种多样的酸(无机和有机两者)形成。酸加成盐的实例包括从以下酸形成的盐,所述酸包括但不限于:乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸(例如L-抗坏血酸)、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、(+)樟脑酸、樟脑-磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡庚糖酸、D-葡糖酸、葡糖醛酸(例如D-葡糖醛酸)、谷氨酸(例如L-谷氨酸)、α-氧代戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、乳酸(例如(+)-L-乳酸、(±)-DL-乳酸)、乳糖酸、马来酸、苹果酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲磺酸、萘磺酸(例如萘-2-磺酸)、萘-1,5-二磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、磷酸、丙酸、L-焦谷氨酸、丙酮酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、单宁酸、(+)-L-酒石酸、硫氰酸、甲苯磺酸(例如对甲苯磺酸)、十一碳烯酸和缬草酸,以及酰化氨基酸和阳离子交换树脂。
盐的一个特定的组由从以下酸形成的盐组成:乙酸、盐酸、氢碘酸、磷酸、硝酸、硫酸、柠檬酸、乳酸、琥珀酸、马来酸、苹果酸、羟乙磺酸、富马酸、苯磺酸、甲苯磺酸、甲磺酸(methanesulphonic、mesylate)、乙磺酸、萘磺酸、戊酸、乙酸、丙酸、丁酸、丙二酸、葡糖醛酸和乳糖酸。酸加成盐的另一个组包括从以下酸形成的盐:乙酸、己二酸、抗坏血酸、天冬氨酸、柠檬酸、DL-乳酸、富马酸、葡糖酸、葡糖醛酸、马尿酸、盐酸、谷氨酸、DL-苹果酸、甲磺酸、癸二酸、硬脂酸、琥珀酸和酒石酸。
如果化合物是阴离子或具有可以是阴离子的官能团(例如,-COOH可以是-COO-),则盐可用合适的阳离子形成。合适的无机阳离子的实例包括但不限于:碱金属离子如Na+和K+、碱土金属阳离子如Ca2+和Mg2+、以及其他阳离子如Al3+。合适的有机阳离子的实例包括但不限于铵离子(即,NH4 +)和经取代的铵离子(例如,NH3R+、NH2R2 +、NHR3 +、NR4 +)。
一些合适的经取代铵离子的实例是衍生自以下的那些:乙胺、二乙胺、二环己胺、三乙胺、丁胺、乙二胺、乙醇胺、二乙醇胺、哌嗪、苄胺、苯基苄胺、胆碱、葡甲胺和氨丁三醇、以及氨基酸,如赖氨酸和精氨酸。常见的季铵离子的实例是N(CH3)4 +。
在化合物含有胺官能团的情况下,这些可形成季铵盐,例如根据技术人员熟知的方法通过与烷化剂进行反应。此类季铵化合物在所披露的化合物的范围内。含有胺官能团的化合物还可以形成N-氧化物。本文提及的含有胺官能团的化合物还包括N-氧化物。当化合物含有若干个胺官能团时,可以将一个或多于一个氮原子氧化形成N-氧化物。N-氧化物的特别的实例是叔胺或含氮杂环的氮原子的N-氧化物。N-氧化物可以通过用氧化剂如过氧化氢或过酸(例如,过氧羧酸)处理相应的胺来形成,参见例如Advanced OrganicChemistry[高等有机化学],Jerry March编辑,第4版,Wiley Interscience[威利国际科学公司],页。更特别地,N-氧化物可以通过L.W.Deady的程序(Syn.Comm.[合成通讯](1977),7,509-514)来制备,其中例如在惰性溶剂如二氯甲烷中,使胺化合物与间氯过氧苯甲酸(MCPBA)反应。
如本文所使用的,术语“溶剂化物”意指化合物与一种或多种溶剂分子的物理结合。这种物理缔合涉及不同程度的离子和共价键合,包括氢键键合。在某些情况下,溶剂化物将能够分离,例如,当一个或多个溶剂分子并入结晶固体的晶格时。术语“溶剂化物”旨在涵盖溶液相和可分离的溶剂化物两者。合适的溶剂化物的非限制性实例包括与水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸或乙醇胺等的组合的所披露的化合物。化合物可在溶液中发挥其生物学作用。
溶剂化物在药物化学中是熟知的。它们对于物质的制备过程(例如,关于它们的纯化)、物质的储存(例如其稳定性)和物质的处理的容易性是重要的并且通常形成化学合成的分离或纯化阶段的一部分。本领域技术人员可以借助于标准的和长期使用的技术确定水合物或其他溶剂化物是否已经通过用于制备给定化合物的分离条件或纯化条件而形成。此类技术的实例包括热重量分析(TGA)、差示扫描量热法(DSC)、X射线结晶学(例如单晶X射线结晶学或X射线粉末衍射)和固态NMR(SS-NMR,也称为魔角旋转NMR或MAS-NMR)。此类技术与NMR、IR、HPLC和MS一样,是熟练的化学家的标准分析工具包的一部分。可替代地,技术人员可以使用结晶条件有意地形成溶剂化物,所述结晶条件包括特定溶剂化物所需的一定量的溶剂。此后,上述标准方法可以用于确定溶剂化物是否形成。还涵盖PRMT5抑制剂的任何复合物(例如与如环糊精的化合物或与金属的络合物的包合络合物或包合物)。
此外,化合物可具有一种或多种多晶型(结晶)或无定形形式。
所述化合物包括具有一个或多个同位素取代的化合物,并且对具体元素的提及包括在其范围内所述元素的所有同位素。例如,对氢的提及包括在其范围内的1H、2H(D)、和3H(T)。类似地,对碳和氧的提及分别包括在其范围内的12C、13C和14C以及16O和18O。所述同位素可以是放射性的或非放射性的。在一个实施例中,化合物不含放射性同位素。此类化合物对于治疗用途是优选的。然而,在另一个实施例中,化合物可以含有一种或多种放射性同位素。含有此类放射性同位素的化合物在诊断的上下文中可以是有用的。
在一些实施例中,如果样品中存在一种或多种U2AF1突变体,则用PRMT5抑制剂治疗患者,其中所述PRMT5抑制剂是化合物2或化合物80、或其药学上可接受的盐或其溶剂化物。
治疗患者癌症的方法
本文披露了治疗患者癌症的方法,所述方法包括:评估来自所述患者的生物学样品中是否存在一种或多种突变或扩增,包括PIC3CA激活突变、剪接体改变、细胞周期蛋白D1途径扩增和/或WNT途径改变;以及如果样品中存在一种或多种突变或扩增(包括PIC3CA激活突变、剪接体改变、细胞周期蛋白D1途径扩增和/或WNT途径改变),则用PRMT5抑制剂治疗患者。
所披露的方法可以用于治疗多种癌症类型,包括但不限于:膀胱癌、转移性膀胱癌、卵巢癌、头颈癌、食道癌、非小细胞肺腺癌、非小细胞肺鳞状细胞癌、前列腺癌、肺癌、胃癌、尿路上皮癌、小细胞肺癌、乳腺癌、子宫内膜癌、胆管癌(choleagiocarcinoma)、胶质母细胞瘤、神经胶质瘤、结肠癌、肉瘤、鳞状起源的实体瘤和多发性骨髓瘤。
在一些实施例中,评估步骤包括:从生物学样品中分离RNA;从分离的RNA合成cDNA;预扩增cDNA;以及用一对引物对预扩增的cDNA进行扩增,所述引物结合并扩增一种或多种突变,包括PIC3CA激活突变、剪接体改变、细胞周期蛋白D1途径扩增和/或WNT途径改变。
从生物学样品中分离RNA可以通过本领域技术人员已知的许多程序进行。在一个实施例中,可以使用来自凯杰公司(Qiagen)的AllPrep DNA/RNA FFPE试剂盒(产品号80234)从生物学样品中分离RNA。
从分离的RNA合成cDNA可以通过本领域技术人员已知的许多程序进行。在一个实施例中,可以使用来自ABI的含RNA酶抑制剂的高容量cDNA逆转录酶试剂盒(产品号4374966)从分离的RNA合成cDNA。
cDNA的预扩增可以通过本领域技术人员已知的许多程序进行。扩增程序是本领域熟知的。在一个实施例中,可以使用PreAmp Master Mix(生命科技公司/应用生物系统公司(Life Technologies/Applied Biosystems)产品号4391128)预扩增cDNA。
合适用于在治疗方法中使用的PRMT5抑制剂包括本文先前描述的那些。鉴定将对用蛋白质精氨酸N-甲基转移酶5(PRMT5)抑制剂治疗有响应的癌症患者的方法
用于鉴定突变体或改变的基因的存在的试剂盒
进一步披露了用于鉴定生物学样品中一种或多种突变或扩增(包括PIC3CA激活突变、剪接体改变、细胞周期蛋白D1途径扩增和/或WNT途径改变)的存在的试剂盒,所述试剂盒包括:具有其组合序列的引物对;和用于进行测定以检测一种或多种突变或扩增(包括PIC3CA激活突变、剪接体改变、细胞周期蛋白D1途径扩增和/或WNT途径改变)的说明书。
当结合附图阅读时,将进一步理解概述以及以下详细说明。出于说明所披露的方法、试剂盒和引物的目的,在附图中显示了方法、试剂盒和引物的示例性实施例;然而,所述方法、试剂盒和引物不限于所披露的具体实施例。
具体实施方式
如实例中使用的PRMT5抑制剂化合物2和80也在PCT/EP2016/070097中例示。
下文中,术语“rt”、“r.t.”或“RT”意指室温;“Me”意指甲基;“MeOH”意指甲醇;“Et”意指乙基;“EtOH”意指乙醇;“NaH”意指氢化钠;“DEAD”意指偶氮二甲酸二乙酯;“HMPT”意指六甲基磷三酰胺;“Boc2O”意指叔丁氧基羰基酸酐;“ButONO”意指亚硝酸叔丁酯;“TosOH”意指4-甲基苯磺酸;“TosCl”意指4-甲基苯磺酰氯(也称对甲苯磺酰氯);“CMBP”意指氰基亚甲基三丁基正膦;“DBAD”意指二-叔丁基偶氮二羧酸酯;“LAH”意指氢化铝锂;“NaBH(AcO)3”或“NaBH(OAc)3”意指三乙酰氧基硼氢化钠;“EtOAc”意指乙酸乙酯;“TEA”或“Et3N”意指三乙胺;“DCM”意指二氯甲烷;“q.s.”意指适量;“Int.”意指中间体;“MeCN”或“ACN”意指乙腈;“DMF”意指N,N-二甲基甲酰胺;“DMA”意指N,N-二甲基乙酰胺;“DMF-DMA”意指N,N-二甲基甲酰胺二甲基缩醛;“Pd(dppf)Cl2”意指[1,1’-双(二苯基膦基)二茂铁]二氯钯(II);“THF”意指四氢呋喃;“C34H28FeP2.Cl2Pd”意指[1,1’-双(二苯基膦基)二茂铁]二氯钯(ii);“i-PrOH”或“iPrOH”意指2-丙醇;“LC”意指液相色谱法;“LCMS”意指液相色谱法/质谱法;“HPLC”意指高效液相色谱法;“int.”意指中间体;“制备型-HPLC”意指制备型高效液相色谱法;“m-CPBA”意指间氯过氧苯甲酸;“TFA”意指三氟乙酸;“m.p.”意指熔点;“RP”意指反相;“Min”意指分钟;“h”意指小时;“PE”意指石油醚;“v/v”意指体积比;意指硅藻土;“DMSO”意指二甲亚砜;“SFC”意指超临界流体色谱法;“DIPE”意指二异丙醚;“dppf”或“DPPF”意指1,1’-双(二苯基膦基)二茂铁;“DIPEA”或“DIEA”意指N,N-二异丙基乙胺;“PPh3”意指三苯基膦;“Et2O”意指二乙醚;“Pd/C”意指在钯碳;“Pt/C”意指铂碳;“Pd(OH)2/C”意指氢氧化钯碳;“CPME”意指环戊基甲基醚;“Pd2(dba)3”意指三(二苯亚甲基丙酮)二钯;“DIAD”意指偶氮二甲酸二异丙酯;“TMSCF3”意指三甲基(三氟甲基)硅烷;“TBAF”意指四丁基氟化铵;“psi”意指磅力每平方英寸;“Et4NCl”意指四乙基氯化铵;“eq.”意指当量;“Pd(OAc)2”意指乙酸钯(II);“AcOH”意指乙酸;“DMAP”意指4-(二甲氨基)吡啶;“t-BuOK”、“tBuOK”或“KOtBu”意指叔丁醇钾;“戴斯-马丁高碘烷(Dess-Martin periodinane)”意指1,1,1-三乙酰氧基-1,1-二氢-1,2-苯碘酰基-3(1H)-酮;“TBDMSCl”意指叔丁基二甲基甲硅烷基氯;“PPh3-聚合物”或“PPh3-pol”意指三苯基膦聚合物结合;“Ph3PCH3Br”意指甲基三苯基溴化鏻;“Bn”意指苄基;“Bz”意指苯甲酰基;“p-TSA”意指4-甲基苯磺酸;“BF3.Et2O”意指三氟化硼-乙醚复合物;“9-BBN”意指9-硼双环[3.3.1]壬烷;“Pd-118”意指二氯[1,1’-双(二叔丁基膦基)二茂铁]钯(II);并且“TLC”意指薄层色谱法;“制备型-TLC”意指制备型TLC;
“p-MeC6H4SO3H.H2O”意指对甲苯磺酸水合物;“PMB”意指对甲氧基苄基;“KOAc”意指乙酸钾;“PTSA”意指对甲苯磺酸;“MTBE”意指甲基叔丁基醚;“Rh(acac)(eth)2”意指乙酰丙酮酰双(亚乙基)铑(I);“(S)-MonoPhos”意指(S)-N,N-二甲基联萘并[2,1-D:1’,2’-F][1,3,2]二氧磷杂环庚二烯-4-胺;“Tf2O”意指三氟甲磺酸酐;“MeI”意指碘代甲烷;“Me2NH”意指二甲胺;“Me2NH.HCl”意指二甲胺盐酸;“Me4NCl”意指四乙基氯化铵;“MeONa”意指甲醇钠;“Ts”意指甲苯磺酰基;“MsCl”意指甲磺酰氯;“DIBAH”意指二异丁基氢化铝;
“TBDMS”意指叔丁基二甲基甲硅烷基;“Pd(dppf)Cl2.CH2Cl2”意指[1,1’-双(二苯膦基)二茂铁]二氯钯(II),与二氯甲烷的复合物;“PPA”意指多磷酸;“NH2Bn”意指苄胺;“Pd(PPh3)2Cl2”意指加二氯双(三苯基膦)钯(II)。
针对在下一个反应步骤中作为粗品或作为部分纯化的中间体被使用的中间体,估计的摩尔量(在一些情况下由≈指示)在下文的反应方案中指示,或者可替代地指示理论上的摩尔量。
中间体1的制备
在25℃,在N2下,向6-氯-7-去氮杂嘌呤β-d-核苷(25.0g,87.5mmol)在丙酮(330mL)中的混合物里一次性添加2,2-二甲氧基丙烷(18.2g,175mmo1)和4-甲基苯磺酸(TosOH)(1.51g,8.75mmol)。将混合物在60℃搅拌2小时。将混合物冷却至25℃。将反应通过缓慢添加饱和NaHCO3(100mL)淬灭并且然后用乙酸乙酯(125mL x5)萃取。将合并的有机相用饱和盐水(120mL)洗涤,用无水MgSO4干燥,过滤并且在真空中浓缩。将残余物通过硅胶色谱法(梯度洗脱:从1∶0至2∶1的DCM/乙酸乙酯)纯化,以得到呈浅黄色胶的粗中间体1(38.0g)。
中间体59的制备
在室温,将偶氮二羧酸二异丙酯(0.221mL,1.125mmol)滴加到中间体1(0.27g,0.80mmol)、3-溴喹啉-7-醇(0.18g,0.80mmol)和三苯基膦树脂(0.375g,3mmol/g,1.125mmol)在THF(8ml)中的搅拌悬浮液中。在添加之后,将反应混合物搅拌18小时。将反应混合物用垫过滤。将残余物用甲醇洗涤。将滤液的溶剂蒸发。将残余物按原样用于下一个步骤中。
中间体105的制备
将粗中间体59(q.s.,理论上为0.83mmol)溶解在MeOH中的7M NH3里(20mL,7M,140mmol)。将所得溶液进行搅拌并在130℃使用微波辐射2小时。蒸发溶剂。将残余物溶解在二氯甲烷中并经SiO2柱纯化,类型为Grace Reveleris SRC,12g,Si 40,在GraceReveleris X2纯化系统上,使用二氯甲烷和甲醇作为洗脱液,梯度从100%DCM的20个柱体积开始,至20个柱体积的20%MeOH和80%DCM。将含有产物的级分合并,并且将溶剂蒸发以产出粗中间体105(175mg),将其按原样用于下一个反应步骤中。
化合物2的制备
在室温,将4M HCl的二恶烷溶液(0.7mL,2.9mmol)添加到中间体105(175.1mg,粗品,≈0.29mmol)在MeOH(10mL)中的搅拌溶液中。将反应混合物在室温搅拌18小时。将反应通过添加1.5mL的NH3在MeOH中的7N溶液淬灭。蒸发溶剂。将残余物溶解于DCM中。过滤出沉淀。将滤液经SiO2柱纯化,类型为Grace Reveleris SRC,12g,Si 40,在Armen Spot IIUltimate纯化系统上,使用DCM和MeOH作为洗脱液,梯度从100%DCM开始,并以40%MeOH和60%DCM结束。将含有产物的级分合并,并且将溶剂蒸发产生24.5mg的化合物2。
中间体10的制备
步骤a)
在25℃,在N2下,向4,6-二氯-5-(2,2-二乙氧基乙基)嘧啶(14.0g,52.8mmol)和(1R,2S,3R,5R)-3-氨基-5-(羟基甲基)环戊烷-1,2-二醇盐酸盐(10.7g,58.1mmol)在丙-2-醇/H2O(208mL,7∶1)中的混合物里一次性添加Et3N(13.4g,132mmol)。将混合物在90℃搅拌23小时。将混合物冷却至50℃并缓慢添加4M HCl(24mL,106mmol)。然后将残余物在50℃搅拌2小时。将反应混合物冷却至25℃,并且缓慢添加NaHCO3(14g,100mmol)。添加乙酸乙酯(230mL),随后添加半饱和NaHCO3溶液(q.s.)。将有机层分离并且将水相用乙酸乙酯(230mLx2)萃取。将合并的有机相用无水MgSO4干燥,过滤并且在真空中浓缩以得到呈黄色固体的中间体9(17.4g,定量产率,分2步)。将粗产物不经进一步纯化而直接原样用于下一个反应步骤中。
步骤b)
在25℃,在N2下,向中间体9(17.4g,≈52.7mmol)在丙酮(250mL)中的混合物里一次性添加2,2-二甲氧基丙烷(11.0g,105mmol)和TsOH.H2O(908mg,5.27mmol)。将混合物在60℃搅拌2小时。将混合物冷却至25℃,并且将溶液在真空中浓缩,用饱和NaHCO3(100mL)缓慢淬灭并然后用乙酸乙酯(100mL x 3)萃取。将合并的有机相用饱和盐水(100mL)洗涤,用无水MgSO4干燥,过滤并且在真空中浓缩。将残余物通过硅胶快速色谱法(梯度洗脱:从1/0至2/1的DCM/乙酸乙酯)纯化,以得到呈浅黄色胶的中间体10(15.5g,89%产率)。
中间体33的制备
在0℃,在N2下,向中间体1(2.00g,理论上为6.18mmol)的DCM(40mL)中的混合物里一次性添加戴斯-马丁高碘烷(5.24g,12.36mmol)。将混合物在0℃搅拌3小时。向混合物中添加在饱和NaHCO3(20mL)中的Na2S2O3(4g)并搅拌10min。将水相用DCM(20mL x3)萃取。将合并的有机相用饱和盐水(20mL x2)洗涤,用无水MgSO4干燥,过滤并且在真空中浓缩,以得到呈浅黄色胶的中间体33(1.80g,粗品)。将粗产物不经进一步纯化而直接用于下一个反应步骤中。
下面的中间体通过与制备中间体33所使用的类似的反应方案,使用适当的起始材料制备(表7)。
表7:
中间体38的制备
方法1
在0℃,在N2下,向甲基三苯基鏻溴化物(4.87g,13.62mmol)在THF(500mL)中的混合物里滴加t-BuOK(11.4mL,在THF中1M,1.27g,11.35mmol)。将悬浮液变为亮黄色并在0℃搅拌0.5h,并且然后温热至25℃,保持0.5h。将混合物冷却至-40℃。滴加中间体35(1.46g,理论上为4.54mmol)在THF(130.0mL)中的溶液,并且然后在-20℃搅拌1h,之后,将混合物温热至25℃,保持2h。向混合物中添加饱和NH4Cl(300ml)并搅拌10min。将各层分离,并将水相用DCM(300mL x2)萃取。将合并的有机相用饱和盐水(500mL)洗涤,用无水MgSO4干燥,过滤并且在真空中浓缩。将残余物通过硅胶色谱法(80g快速硅胶柱,梯度洗脱:从0至15%乙酸乙酯/石油醚)纯化。收集所希望的级分并将溶剂蒸发。获得中间体38,呈灰白色固体(530mg,36%产率)。
方法2:
中间体38
在N2下,在30分钟内,向中间体35(10.0g,理论上为31.1mmol)在THF(100mL)中的溶液里滴加双(碘代)甲烷在THF中的溶液(180mL,0.31M,55.9mmol,根据Tetrahedron[四面体]2002,58,8255-8262中描述的方法制备),继续搅拌直至完全转化(约2小时)。将反应混合物通过缓慢添加饱和水性NH4Cl溶液淬灭,在这期间可以观察到盐的形成。在萃取(EtOAc,2x 200mL)之前,将盐再次通过添加氨水溶液(25%)溶解。将合并的有机相用水性亚硫酸氢钠溶液和盐水洗涤,用无水MgSO4干燥,过滤并且在真空中浓缩。将残余物通过硅胶色谱法(洗脱液:二氯甲烷/EtOAc 95/5)纯化,以提供呈灰白色固体(6.9g,66%)的中间体38。
中间体174的制备
将3-溴-7-碘-喹啉(5.99g,17.7mmol)溶解在二氯甲烷(60mL)中,然后分批添加m-CPBA(4.57g,26.5mmol)。在室温将混合物搅拌4天。将混合物用饱和Na2S2O3水溶液(40mL)和饱和NaHCO3水溶液(PH至6-7)淬灭,然后用二氯甲烷(50mL x3)萃取。将有机相用H2O(50mL)洗涤,用无水Na2SO4干燥并在减压下蒸发。将残余物通过硅胶柱(洗脱液:石油醚/乙酸乙酯=10/1至1/1)纯化,以得到呈黄色固体的所希望的产物中间体174(1.9g,14.1%产率)。
中间体175的制备
向中间体174(2.9g,8.29mmol)在氯仿(60mL)中的溶液里添加三氯化磷酰(8.3g,54.1mmol)。将混合物在80℃搅拌12h。在减压下蒸发混合物,以获得粗产物。将粗产物通过色谱法柱(洗脱液:石油醚/乙酸乙酯=10/1至1/1)纯化。将所希望的级分进行收集和浓缩,以给出呈白色固体的产物中间体175(1.3g,41.5%产率)。
中间体176的制备
将4-甲氧基苯胺(1.34g,9.78mmol)添加至中间体175(0.8g,≈1.95mmol)在乙醇(10ml)中的混合物里。将混合物在100℃在密封管中加热12h。将混合物在真空下蒸发,以获得粗产物。将粗产物通过色谱法柱(梯度洗脱液:乙酸乙酯/石油醚从0/1至1/10)纯化。将所希望的级分进行收集和浓缩,以给出呈油状的产物中间体176(600mg,51.6%产率)。
中间体177的制备
将中间体38(44mg,0.138mmol)在9-BBN(1.3ml,0.69mmol,在THF中0.5M)中的混合物在N2下回流1h。将混合物冷却至室温,然后添加在H2O(1mL)中的K3PO4(87mg,0.413mmol),随后添加THF(5ml)、中间体176(122.727mg,≈0.206mmol)以及[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(4.48mg,0.007mmol)。将反应混合物回流3小时。将混合物浓缩。将残余物溶解在乙酸乙酯(40ml)中,用水(6ml)、盐水(6ml)洗涤。将有机相经Na2SO4干燥,过滤并且浓缩,以给出粗中间体177级分1(120mg,71.5%产率)。
将中间体38(233.7mg,0.73mmol)在9-BBN(7.31ml,3.65mmol,在THF中0.5M)中的混合物在N2下回流1h。将混合物冷却至室温,然后添加在H2O(1mL)中的K3PO4(87mg,0.413mmol),随后添加THF(5ml)、中间体176(478mg,≈0.80mmol)以及[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(23.8mg,0.037mmol)。将反应混合物回流3小时。将混合物浓缩。将残余物溶解在乙酸乙酯(40ml)中,用水(6ml)、盐水(6ml)洗涤。将有机相经Na2SO4干燥、过滤并且浓缩以给出粗中间体177级分2(600mg,63.1%产率)。
将这两种级分合并,并且通过色谱法柱(梯度洗脱液:乙酸乙酯/石油醚从1/10至1/1)纯化。将所希望的级分进行收集和浓缩,以给出呈固体的中间体177(300mg,61.0%产率)。
中间体178的制备
将中间体177(300mg,≈0.446mmol)和NH3.H2O(10ml)在二噁烷(10ml)中的混合物在120℃在密封管中搅拌14h。将反应物在真空下蒸发,以获得呈油状的中间体178(250mg,87.1%产率)。
中间体179的制备
在50℃将中间体178(250mg,≈0.388mmol)在TFA(5ml)中的混合物搅拌1h。将混合物在真空下蒸发,以获得呈油状的中间体179(350mg,63.4%产率)。
化合物80的制备
将中间体179(350mg)和K2CO3(102mg,0.74mmol)在甲醇(3mL)中的混合物在60℃搅拌1h。将混合物过滤并且在真空下蒸发,以获得粗产物。将粗产物通过制备型-HPLC(柱:Waters Xbridge Prep OBD C18 150x30mm,5μm,条件:梯度水(0.05%氢氧化氨v/v)-ACN)纯化。将所希望的级分进行收集并且将溶剂蒸发以给出呈白色固体的化合物80(113.3mg,94.9%产率)。
分析部分
NMR
对于许多化合物来说,将1H NMR光谱在以360MHz操作的Bruker DPX-360上,在以600MHz操作的Bruker Avance 600上,在以400MHz操作的Bruker Avance 400上,或者在以400MHz操作的Varian400MR分光仪上进行记录。将氯仿-d(氘化氯仿,CDCl3)、甲醇-d4或DMSO-d6(氘化DMSO,二甲基-d6亚砜)用作溶剂。将化学位移(δ)报告为相对于四甲基硅烷(TMS)(用作内部标准)的百万分率(ppm)。
Co.80:1H NMR(600MHz,DMSO-d6)δppm 1.50-1.56(m,1H)1.68-1.75(m,1H)1.85-1.92(m,1H)1.96(ddt,J=13.0,9.0,6.5,6.5Hz,1H)2.25(dt,J=12.7,7.9Hz,1H)2.69-2.80(m,2H)3.76(br t,J=4.7Hz,1H)4.21(dd,J=7.6,6.0Hz,1H)4.57(br s,1H)4.72(brs,1H)4.80(dt,J=10.5,7.9Hz,1H)6.50(br s,2H)6.59(d,J=3.5Hz,1H)7.07(br s,2H)7.12(dd,J=8.2,1.6Hz,1H)7.29(d,J=3.6Hz,1H)7.34(s,1H)7.58(d,J=8.1Hz,1H)8.07(s,1H)8.31(s,1H)。
体外测定实验程序(测定1a和1b)
试剂
从查尔斯河(阿根塔)(Charles River(Argenta))购买PRMT5-MEP50酶。酶复合体产生于同时用两种杆状病毒感染的昆虫细胞(Sf9)中。一种病毒表达在N-端具有Flag标签的全长人PRMT5,第二种病毒表达在N-端具有His6-TEV切割的全长MEP50。使用以3xFLAG肽洗脱的抗-Flag(M2)珠球对蛋白质进行亲和纯化,随后用以0.5M咪唑洗脱的His-Select进行亲和纯化。然后将洗脱的蛋白质用含有20%甘油和3mM二硫苏糖醇(DTT)的tris-缓冲盐水(TBS)(pH8.0)进行透析。
从反应生物公司(Reaction Biology Corporation,目录号HMT-11-146)购买在大肠杆菌中表达的全长未标记的人重组组蛋白H2A(残基1-130,Genbank登录号NM_021052,MW=14.1kDa)。用于使反应缓冲或停止反应的试剂是购买的,所述试剂包括Tris碱(西格玛公司(Sigma),目录号T-1503)、NaCl(西格玛公司,目录号RGF-3270)、MgCl2(西格玛公司,目录号M0250),DTT(英杰公司(Invitrogen),目录号15508-013)以及甲酸(卡尔-菲修公司(Riedel deHaen),目录号33015)
高通量质谱仪测定
PRMT5在蛋白质内的精氨酸残基的胍基上使用共-底物S-腺苷-L-甲硫氨酸(AdoMet,SAM)对末端氮原子的顺序甲基化进行催化,形成单-甲基(MMA),对称-二甲基精氨酸(sDMA)和S-腺苷-L-高半胱氨酸(AdoHcy,SAH)。通过使用高通量质谱法(AgilentRapidfire 300系统偶联至Sciex 4000系列三重四极杆MS/MS)跟踪产物SAH形成来确定酶活性。反应缓冲液为20mM Tris-HCl,pH 8.5,50mM NaCl,5mM MgCl2以及1mM DTT。使用1%的甲酸(最终浓度)终止反应活性。
抑制研究。使用在二甲基亚砜(DMSO)中1∶2连续稀释的每种化合物制备的11点给药系列进行IC50研究,其中点12为DMSO对照。将化合物首先点样在板上,接着添加2μM SAM和0.6μM H2A(组蛋白H2A)的溶液混合物。添加相同体积的酶溶液以启动酶促反应。反应的最终浓度为1μM SAM,0.3μM H2A和10nM酶(测定1a)或1.25nM酶(测定1b)。将反应在30℃进行孵育,当使用10nM酶时持续60分钟(min),并且当使用1.25nM酶时持续120min。随后,将反应通过添加甲酸淬灭以得到最终浓度为1%。在所述化合物的存在下将对SAH形成的抑制作用计算为相对于未受抑制的反应为抑制剂浓度函数的对照的百分比。数据拟合如下:
Y=底部+(顶部-底部)/(1+10^((log IC50-X)*h))
其中IC50是在50%抑制时的抑制剂浓度(与X单位相同)并且h是Hill斜率。Y是抑制百分比,X是化合物浓度的对数。底部和顶部是与Y具有同样单位的平台。
下表1中的pIC50值是平均值(Co No.意指化合物编号)。
表1
实例1:PIK3CA激活突变与SCLC中的PRMT5抑制剂敏感性相关。
在广泛肺癌细胞系组的SCLC亚分类中评估化合物2的细胞敏感性谱。引人注目的是,一些最敏感的细胞系携带在PIK3Cα基因中的不同的功能获得性突变,并在表2中提及。PI3Kα途径(功能获得性突变或途径刺激)作为对标准治疗(顺铂)或甚至对靶向药物(像最新一代PARP抑制剂)的肿瘤响应而激活暗示了在抗性过程中的关键作用,这可能与治疗后SCLC患者的总体存活低相关联。
细胞系 | PIK3CA突变 | 组织学亚型 | GI50 |
NCI-H1048 | H1047R | SCLC | 94.62nM |
LU99a | T1025A | SCLC | 128.53nM |
H69V | G106_R108del | SCLC | 85.62nM |
表2
实例2:在NSCLC中,剪接体改变与PRMT5抑制剂敏感性相关
已知癌症特异性剪接事件引发恶性肿瘤并且还有助于疾病进展。到目前为止,已经描述了参与剪接的两种蛋白U2AF1和RBM10在NSCLC中是错误调控的。
U2AF1是一种表征良好的剪接因子,在3%-8%的NSCLC患者中携带功能获得性热点突变(S34F)。最近,RNA结合蛋白RBM10(其对于剪接体的组装也是至关重要的)已经被归类为通过功能丧失性突变(主要在具有吸烟史的NSCLC患者(约8%)中)而失活的肿瘤抑制因子。
已经将对剪接体组装至关重要的Sm蛋白描述为PRMT5的直接底物,并且因此,PRMT5功能与调节剪接体活性相关联。
由于U2AF1中的S34F功能获得性突变已经被确认为是致癌的,因此组装了一小组携带S34F突变的所有可商购的NSCLC细胞系,以分析U2AF1-S34F和PRMT5抑制之间潜在的合成致死关系。
携带热点突变的所有(三分之三)NSCLC细胞对PRMT5抑制剂化合物2具有增殖敏感性,参见表3。
细胞系 | 基因/突变 | 组织学亚型 | GI50 |
NCI-H441 | U2AF1-S34F | 腺癌 | 98.40nM |
LC-2/ad | U2AF1-S34F | 腺癌 | 116.08nM |
HCC78 | U2AF1-S34F | 腺癌 | 107.65nM |
表3
实例3:细胞周期蛋白D1途径扩增与NSCLC中PRMT5抑制剂敏感性相关
已报道了多种癌症(包括NSCLC)中G1细胞周期蛋白家族的扩增和/或增加的表达。已经观察到PRMT5与细胞周期调控剂(包括细胞周期蛋白D1、CDK4和CDK6)的表达之间的相关性,这表明PRMT5可能对G1期具有调控作用。对用化合物2处理的肺细胞系组的分析揭示了细胞周期蛋白D1/CDK4/CDK6扩增和PRMT5i-敏感性之间的显著关联,这指示细胞周期蛋白途径畸变可以用作患者选择的标志。表4显示携带此类细胞周期蛋白D1/CDK4/CDK6扩增的NSCLC细胞系对用化合物2处理敏感。
细胞系 | 扩增的基因 | 组织学亚型 | GI50 |
EPLC272H | 细胞周期蛋白D1 | 腺癌 | 98.53nM |
NCI-H226 | CDK4 | 腺癌 | 204.52nM |
HLC1 | CDK6 | 鳞状细胞癌 | 96.39nM |
表4
实例4:WNT途径改变与PRMT5抑制剂敏感性相关
携带关键Wnt信号转导基因(包括β-连环蛋白和APC)中突变的细胞系对PRMT5i处理显示出敏感性,如表5所示
细胞系 | 基因/突变 | 组织学亚型 | GI50 |
A427 | CTNNB1/T41A | 腺癌 | 166.52nM |
HCC15 | CTNNB1/S45F,Y670* | 鳞状细胞癌 | 266.07nM |
LK2 | APC/W685*,E1020K | 鳞状细胞癌 | 114.53nM |
表5
实例
本领域技术人员将理解,可以对本发明的优选的实施例进行许多改变和修改,并且可以在不脱离本发明的精神的情况下进行此类改变和修改。因此,所附权利要求旨在覆盖落入本发明的真实精神和范围内的所有此类等效变化。
在本文件中引用或描述的每个专利、专利申请和出版物的披露内容通过引用以其整体特此并入本文。
Claims (7)
1.一种鉴定患者的方法,所述患者可能对用蛋白质精氨酸N-甲基转移酶5(PRMT5)抑制剂治疗有响应,所述方法包括:
评估来自所述患者的生物学样品中是否存在剪接体改变,
其中任何所述改变的存在指示相比不存在任何所述改变,所述患者对用所述PRMT5抑制剂治疗有响应的可能性更高。
2.如权利要求1所述的方法,其中,所述剪接体改变包含选自由以下组成的组的基因中的突变:U2AF1、RBM10和KIAA1429。
3.如权利要求2所述的方法,其中,所述基因是U2AF1,并且所述突变是S34F。
4.如权利要求2所述的方法,其中,所述基因是RBM10,并且所述突变选自由以下组成的组:I696fs、I348N和G840fs。
5.如权利要求2所述的方法,其中,所述基因是KIAA1429,并且所述突变选自由以下组成的组:L837V、F1260L、D251if、T1333M、V1548L、G397A和Q962E。
6.如权利要求1-5中任一项所述的方法,其中,所述生物学样品包含剪接体改变,并且所述患者患有NSCLC。
7.如前述权利要求中任一项所述的方法,其中,所述PRMT5抑制剂是化合物2或化合物80。
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IL268842A (en) | 2019-10-31 |
EA201992026A1 (ru) | 2020-01-24 |
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JOP20190199B1 (ar) | 2023-09-17 |
IL268842B1 (en) | 2024-05-01 |
JP7225106B2 (ja) | 2023-02-20 |
US11279970B2 (en) | 2022-03-22 |
JOP20190199A1 (ar) | 2019-08-27 |
EP3585904C0 (en) | 2023-11-29 |
PE20191359A1 (es) | 2019-10-01 |
MA47594A (fr) | 2020-01-01 |
CO2019008390A2 (es) | 2019-08-20 |
KR20190122677A (ko) | 2019-10-30 |
JP2020508048A (ja) | 2020-03-19 |
SG11201907607VA (en) | 2019-09-27 |
BR112019017466A2 (pt) | 2020-03-31 |
MY195860A (en) | 2023-02-24 |
CL2019002438A1 (es) | 2019-11-29 |
EP3585904B1 (en) | 2023-11-29 |
US20200010881A1 (en) | 2020-01-09 |
TN2019000212A1 (en) | 2021-01-07 |
MX2019010150A (es) | 2019-10-21 |
KR102573149B1 (ko) | 2023-08-30 |
UA127679C2 (uk) | 2023-11-29 |
US20220205026A1 (en) | 2022-06-30 |
WO2018154104A1 (en) | 2018-08-30 |
AU2018225312B2 (en) | 2024-02-08 |
EP3585904A1 (en) | 2020-01-01 |
PH12019501942A1 (en) | 2020-06-29 |
CA3049739A1 (en) | 2018-08-30 |
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