CN113698435B - 一类含有p53-MDM2抑制剂的四价铂配合物及其制备方法与应用 - Google Patents
一类含有p53-MDM2抑制剂的四价铂配合物及其制备方法与应用 Download PDFInfo
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- CN113698435B CN113698435B CN202110984574.7A CN202110984574A CN113698435B CN 113698435 B CN113698435 B CN 113698435B CN 202110984574 A CN202110984574 A CN 202110984574A CN 113698435 B CN113698435 B CN 113698435B
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- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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- Organic Chemistry (AREA)
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了一类含有p53‑MDM2抑制剂的四价铂配合物及其制备方法与应用,将p53‑MDM2抑制剂与顺铂连接,构建得到一类含有p53‑MDM2抑制剂的四价铂配合物。利用四价铂配合物的优势,发挥p53‑MDM2抑制剂与顺铂协同抗肿瘤效果。本发明报道的含有p53‑MDM2抑制剂的四价铂配合物,表现广谱、优异的体外抗肿瘤活性,对肺癌A549、胰腺癌Panc‑1、胰腺癌CFPAC‑1、骨肉瘤SJSA‑1、顺铂耐药肺癌、乳腺癌和肝癌均产生了较为明显的增殖抑制作用,部分化合物的抗肿瘤活性明显优于顺铂,可作为抗肿瘤的候选药物进行新药开发。
Description
技术领域
本发明属于医药技术领域,具体涉及一类含有p53-MDM2抑制剂的四价铂配合物、制备方法及其在制备抗肿瘤药物中的应用。
背景技术
铂类抗肿瘤药物在临床上广泛用于恶性肿瘤的治疗。目前,已批准三种铂类药物上市,包括顺铂、卡铂和奥沙利铂。顺铂临床上对卵巢癌、前列腺癌、睾丸癌、肺癌、鼻咽癌、食道癌、恶性淋巴瘤、头颈部鳞癌、甲状腺癌及成骨肉瘤等多种实体肿瘤均能显示疗效。卡铂是第二代铂类药物,为广谱抗肿瘤药,与其他抗肿瘤药无交叉耐药性,与顺铂有交叉耐药性,主要用于小细胞肺癌、卵巢癌、睾丸肿瘤、头颈部鳞癌等。奥沙利铂是第三代铂类药物,对大肠癌、卵巢癌有较好疗效,对胃癌、非霍奇金淋巴瘤、非小细胞肺癌、头颈部肿瘤有一定疗效。铂类抗肿瘤药物是我国肿瘤病人使用最为广泛的化疗药物,但长期使用易产生耐药性、并存在肾毒性、胃肠道不良反应、血液毒性等副作用。将二价的铂类药物氧化成四价铂,进一步在结构上引入其他抗肿瘤药效基团是近年来铂类抗肿瘤药物的热点研发领域。四价铂具有更好的代谢稳定性,能够降低铂类药物的毒性,同时其它药效基团的引入可以发挥多机制、多靶点的协同抗肿瘤效果,解决铂类药物的耐药性。文献已报道抗炎药物如阿司匹林、萘普生等引入到四价铂中会发挥很好的协同抗肿瘤效果,具有毒副作用低、裸鼠体内抗肿瘤效果更优等优势。
p53蛋白是一种重要的肿瘤抑制因子,具有抑制肿瘤细胞生长、修复损伤DNA、诱导细胞凋亡和衰老等重要作用。细胞在应激条件下(如DNA损伤、致癌基因激活或细胞缺氧等),p53基因激活表达p53蛋白,调控下游多个靶基因(如BAX,p21,FAS和PUMA等)的转录,通过p53信号通路发挥抗肿瘤重要作用。此外p53蛋白还能够调节胱氨酸代谢和活性氧应答,引起肿瘤细胞的铁死亡。统计数据表明,肿瘤的生长、恶化与p53功能的丧失或削弱密切相关。大约50%的恶性肿瘤会发生p53基因突变或缺失;剩下约50%的恶性肿瘤则保留野生型p53,但其抑癌功能失活,研究证实肿瘤细胞过表达MDM2蛋白是其失活的最主要原因。MDM2蛋白是p53最主要的负反馈调节子,在多种恶性实体瘤中过表达。研究证实,其过表达与肿瘤的转移和恶化密切相关。MDM2蛋白直接结合并阻断p53的反式激活结构域,促进p53从细胞核外排到细胞质,通过其E3泛素连接酶活性诱导p53被26S蛋白酶体降解,进而丧失p53肿瘤抑制的功能。因此,p53-MDM2抑制剂可以阻断p53和MDM2的蛋白-蛋白相互作用,重新激活和恢复p53抗肿瘤功能。
目前,p53-MDM2抑制剂已广泛开展临床抗肿瘤试验研究,多项肿瘤研究取得积极结果,显示p53-MDM2抑制剂能有效抑制肿瘤生长,有希望成为一种广谱抗肿瘤的靶向药。但现有研究结果表明,p53-MDM2抑制剂对p53突变的肿瘤株抑制效果较差,并能够诱发肿瘤细胞产生获得性耐药,这限制了临床进一步开发应用。
发明内容
为了克服现有技术中p53-MDM2抑制剂只对部分肿瘤细胞系有效、易产生耐药性及二价铂类药物的缺点(肾毒性、耳毒性及易产生耐药性等),本发明的目的在于提供一类含有p53-MDM2抑制剂的四价铂配合物及其制备方法与应用。
为了达到上述目的,本发明采用以下技术方案予以实现:
本发明公开了一类含有p53-MDM2抑制剂的四价铂配合物,结构如通式I所示:
其中,R为H、另一分子的p53-MDM2抑制剂或非甾体抗炎药;
R1为支链或直链的饱和的C1~C20烷基,或者为支链或直链的不饱和的C1~C20烷基。
优选地,R1为-CF3、-CH3、-CH2CH3、-CH(CH3)2、-(CH2)2CH3、-(CH2)4CH3、-(CH2)5CH3、-(CH2)6CH3、-(CH2)10CH3、-(CH2)12CH3、-(CH2)13CH3、-CH=CHCH3或-(CH2)7CH=CH(CH2)7CH3。
优选地,所述非甾体抗炎药包括阿司匹林、萘普生、吲哚美辛和布洛芬。
优选地,所述含有p53-MDM2抑制剂的四价铂配合物为下述化合物中的一种:
本发明还公开了上述的含有p53-MDM2抑制剂的四价铂配合物在制备抗肿瘤药物中的应用。
优选地,所述肿瘤为肺癌、胰腺癌、骨肉瘤、顺铂耐药的肺癌、乳腺癌和肝癌。
本发明还公开了一种产品,其活性成分为上述的含有p53-MDM2抑制剂的四价铂配合物,所述产品的用途至少包括下述用途中的一种:
a)抑制肿瘤细胞增殖;
b)协同增强顺铂抗肿瘤活性;
所述产品为药物、添加剂或活性成分剂。
优选地,所述活性成分为下述的化合物之一:
本发明还公开了上述的含有p53-MDM2抑制剂的四价铂配合物的制备方法,包括以下步骤:
1)将顺铂即化合物II加入过量的30%的双氧水,在20~60℃的条件下反应1~4h,抽滤,滤液静置,得到黄色针状固体即化合物III;
2)将摩尔比为1:1.3:1.3的化合物IV、TBTU和三乙胺依次加入干燥的DMF中,室温搅拌1~30min,再加入化合物III,化合物III与化合物IV的摩尔比为1:1,氮气保护下室温搅拌1~16h,反应结束后,蒸干溶剂,残留物用硅胶柱层析进行纯化,得到化合物V;
3)将摩尔比为1:1.1的化合物V和酸酐或异氰酸酯依次加入DMF中,在室温下搅拌反应1~16h;反应结束后,蒸干溶剂,残留物用硅胶柱层析进行纯化,得到R基团为的化合物I;
或者,
将摩尔比为1:1的化合物V和化合物IV依次加入DMF中,加入HBTU(2equiv)和DIPEA(2equiv),在室温下搅拌反应1~16h;反应结束后,蒸干溶剂,残留物用硅胶柱层析进行纯化,得到R基团为另一分子MDM2抑制剂的化合物10;
或者,
将摩尔比为1:1.1的化合物V和非甾体抗炎药依次加入DMF中,加入HBTU(2equiv)和DIPEA(2equiv),在室温下搅拌反应1~16h;反应结束后,蒸干溶剂,残留物用硅胶柱层析进行纯化,得到R基团为非甾体抗炎药的化合物9。
优选地,所述酸酐为乙酸酐、三氟乙酸酐、正己酸酐、正辛酸酐、月桂酸酐、肉豆蔻酸酐、棕榈酸酐、油酸酐;
所述异氰酸酯为异氰酸己酯、异氰酸辛酯、异氰酸十二烷基酯。
与现有技术相比,本发明具有以下有益效果:
本发明公开的一类含有p53-MDM2抑制剂的四价铂配合物,将二价铂氧化构建四价铂类,同时引入p53-MDM2抑制剂,一方面增强了铂类药物的血浆代谢稳定性,利用肿瘤细胞内高还原性特点,特异性还原四价铂到二价铂发挥DNA损伤抗肿瘤活性;另一方面引入的p53-MDM2抑制剂能够释放正常功能的p53蛋白,进一步诱导肿瘤细胞发生凋亡作用,解决铂类药物的耐药性。本发明报道的含有p53-MDM2抑制剂的四价铂配合物,表现广谱、优异的体外抗肿瘤活性。抗肿瘤构效关系表明,侧链R基团能够明显影响抗肿瘤活性,当R基团为乙酰基、三氟乙酰基、正己酰基、正辛酰基或萘普生时,活性明显优于顺铂、p53-MDM2抑制剂及顺铂与p53-MDM2抑制剂1:1混合使用,因此具有开发成广谱抗肿瘤新药的巨大潜能。
具体实施方式
为了使本技术领域的人员更好地理解本发明方案,下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分的实施例,而不是全部的实施例。本发明术语“包括”和“具有”以及他们的任何变形,意图在于覆盖不排他的包含,例如,包含了一系列步骤或单元的过程、方法、系统、产品或设备不必限于清楚地列出的那些步骤或单元,而是可包括没有清楚地列出的或对于这些过程、方法、产品或设备固有的其它步骤或单元。
下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。
一、制备化合物
实施例1
化合物1的合成:
取1.0g顺铂即化合物II加入25mL 30%的双氧水,在60℃下反应2h,抽滤,滤液静置得到0.95g黄色针状固体氧铂即化合物III,收率为85%。反应方程式如下:
将化合物IV(20mg,0.032mmol)、化合物III(11mg,0.032mmol)、TBTU(13mg,0.0416mmol)和三乙胺(4.2mg,0.042mmol)依次加入2mL干燥的DMF中,在室温下搅拌过夜。反应结束后,蒸干溶剂,残留物用硅胶柱层析(DCM:MeOH=20:1)进行纯化,得到化合物1(即下述方程式中的化合物V),白色固体(18mg,收率58%)。
反应方程式如下:
实施例2
化合物2的合成:
将化合物1(30mg,0.032mmol)与乙酸酐(3.6mg,0.035mmol)在DMF(2mL)中反应,反应12h后,蒸干溶剂,残留物用硅胶柱层析进行纯化,得到白色固体化合物2(24mg,收率76%)。反应方程式如下:
实施例3
化合物3的合成:
参照实施例2,将化合物1(30mg,0.032mmol)与三氟乙酸酐(7.5mg,0.035mmol)在DMF(2mL)中反应,得到白色固体化合物3(25mg,收率75%)。
反应方程式如下:
实施例4
化合物4的合成:
参照实施例2,化合物1(30mg,0.032mmol)与正己酸酐7.5mg,0.035mmol)在DMF(2mL)中反应,得到白色固体化合物4(27mg,收率81%)。反应方程式如下:
实施例5
化合物5的合成:
参照实施例2,化合物1(30mg,0.032mmol)与正辛酸酐(9.6mg,0.035mmol)在DMF(2mL)中反应,得到白色固体化合物5(25mg,收率73%)。反应方程式如下:
实施例6
化合物6的合成:
参照实施例2,化合物1(30mg,0.032mmol)与棕榈酸酐(17.5mg,0.035mmol)在DMF(2mL)中反应,得到白色固体化合物6(27mg,收率72%)。反应方程式如下:
实施例7
化合物7的合成:
参照实施例2,化合物1(30mg,0.032mmol)与油酸酐(19mg,0.035mmol)在DMF(2mL)中反应,得到白色固体化合物7(30mg,收率78%)。反应方程式如下:
实施例8
化合物8的合成:
参照实施例2,化合物1(30mg,0.032mmol)与十二烷基异氰酸酯(7.5mg,0.035mmol)在DMF(2mL)中反应,得到白色固体化合物8(25mg,收率68%)。反应方程式如下:
实施例9
化合物9的合成
在HBTU(24mg,0.064mmol)和DIPEA(8.2mg,0.064mmol)作用下,化合物1(30mg,0.032mmol)与萘普生(8.5mg,0.035mmol)在DMF(2mL)中反应,得到白色固体化合物9(21mg,收率57%)。反应方程式如下:
实施例10
化合物10的合成:
化合物1(30mg,0.032mmol)和另一分子的MDM2抑制剂IV(20mg,0.032mmol)在DMF(2mL)中,加入HBTU(24mg,0.064mmol)和DIPEA(8.2mg,0.064mmol),在室温下搅拌反应12h;反应结束后,蒸干溶剂,残留物用硅胶柱层析进行纯化,得到淡黄色固体化合物10(32mg,收率65%)。反应方程式如下:
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以下实施例制备的化合物的化学结构式、1H-NMR、13C-NMR和HRMS数据详见表1,其中编号1~10分别对应实施例1~10制备的化合物1~10。
表1.目标化合物R1~R10的化学结构式、1H-NMR、13C-NMR和HRMS数据
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二、本发明化合物的抗肿瘤活性试验
对本发明的化合物进行肿瘤细胞增殖抑制试验,试验方法采用常规的CKK-8法。
细胞株选用肺癌A549、胰腺癌Panc-1、胰腺癌CFPAC-1、骨肉瘤SJSA-1、顺铂耐药的肺癌A549和乳腺癌MDA-MB-231,均购自上海生命科学研究院细胞库。培养液为DMEM+10%NBS+双抗。
样品液配制:待测化合物用DMSO(Merck)溶解后,配成浓度为10mM的母液。用培养基稀释母液,配成药物的最终浓度分别为50μM、25μM、10μM、5μM、1μM、0.5μM、0.25μM和0.125μM。
96孔板每孔加入浓度为8×104个/mL的细胞悬液100μL,即8000个细胞/孔,置37℃、5%CO2培养箱内。24小时后,上层培养液吸掉,加入含有样品的培养液和对照品液,100μL/孔,37℃作用72小时。每孔加入CKK-8 10μL,置培养箱内,作用1小时后用MK-2全自动酶标仪测570nm OD值,计算半数抑制浓度IC50。
部分优选化合物的抗肿瘤活性详见表2,其中,样品1~10是指相应实施例中制备的含有p53-MDM2抑制剂的四价铂配合物,如化合物1表示在实施例1中所得到的化合物,同理类推。阳性药为p53-MDM2抑制剂(实施例1中的化合物IV)、顺铂(CDDP)及顺铂与p53-MDM2抑制剂1:1混合(CDDP+IV)。
表2.本发明部分化合物对肿瘤细胞的半数抑制浓度IC50(单位:μM)
表2中结果显示,本申请的化合物总体表现出广谱、优异的抗肿瘤活性,对肺癌A549、胰腺癌Panc-1、胰腺癌CFPAC-1、骨肉瘤SJSA-1、乳腺癌MDA-MB-231和肝癌HepG2均产生了优异的增殖抑制作用。部分化合物的抗肿瘤活性强于顺铂。如化合物4总体表现出最优的抗肿瘤活性,对肺癌A549、胰腺癌Panc-1、胰腺癌CFPAC-1、骨肉瘤SJSA-1、乳腺癌MDA-MB-231和肝癌HepG2的半数抑制浓度IC50都低于3μM。而且,本申请的化合物对骨肉瘤SJSA-1细胞的半数抑制浓度IC50都低于2μM,抗肿瘤活性明显优于顺铂。部分高活性化合物对顺铂耐药的A549肿瘤细胞仍表现优异的抗肿瘤活性。如化合物3、4、5和9对顺铂耐药的A549的IC50均低于5μM,明显优于顺铂(IC50=31.47μM)。此外,这类化合物的抗肿瘤活性要优于IV与顺铂的联用。因此,本发明提供的化合物具有全新的骨架结构,具有优异的抗肿瘤活性,可以进行抗肿瘤药物的开发。
以上所述仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,虽然本发明已以较佳实施例揭露如上,然而并非用以限定本发明,任何熟悉本专利的技术人员在不脱离本发明技术方案范围内,当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例,但凡是未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明方案的范围内。
Claims (9)
1.一类含有p53-MDM2抑制剂的四价铂配合物,其特征在于,结构如通式I所示:
其中,R为H、
R1为支链或直链的饱和的C1~C20烷基,或者为支链或直链的不饱和的C1~C20烷基。
2.根据权利要求1所述的一类含有p53-MDM2抑制剂的四价铂配合物,其特征在于,R1为-CH3、-CH2CH3、-CH(CH3)2、-(CH2)2CH3、-(CH2)4CH3、-(CH2)5CH3、-(CH2)6CH3、-(CH2)10CH3、-(CH2)12CH3、-(CH2)13CH3、-CH=CHCH3或-(CH2)7CH=CH(CH2)7CH3。
3.一类含有p53-MDM2抑制剂的四价铂配合物,其特征在于,所述含有p53-MDM2抑制剂的四价铂配合物为下述化合物中的一种:
4.权利要求1-2中任意一项或权利要求3所述的含有p53-MDM2抑制剂的四价铂配合物在制备抗肿瘤药物中的应用。
5.如权利要求4所述的应用,其特征在于,所述肿瘤为肺癌、胰腺癌、骨肉瘤、乳腺癌和肝癌。
6.一种产品,其特征在于,其活性成分为权利要求1~2中任意一项或者权利要求3所述的含有p53-MDM2抑制剂的四价铂配合物,所述产品的用途至少包括下述用途中的一种:
a)抑制肿瘤细胞增殖;
b)协同增强顺铂抗肿瘤活性;
所述产品为药物、添加剂或活性成分剂。
7.如权利要求6所述的产品,其特征在于,所述活性成分为下述的化合物之一:
8.权利要求1~2中任意一项或者权利要求3所述的含有p53-MDM2抑制剂的四价铂配合物的制备方法,其特征在于,包括以下步骤:
1)将顺铂即化合物II加入过量的30%的双氧水,在20~60℃的条件下反应1~4h,抽滤,滤液静置,得到黄色针状固体即化合物III;
2)将摩尔比为1:1.3:1.3的化合物IV、TBTU和三乙胺依次加入干燥的DMF中,室温搅拌1~30min,再加入化合物III,化合物III与化合物IV的摩尔比为1:1,氮气保护下室温搅拌1~16h,反应结束后,蒸干溶剂,残留物用硅胶柱层析进行纯化,得到化合物V;
3)将摩尔比为1:1.1的化合物V和酸酐或异氰酸酯依次加入DMF中,在室温下搅拌反应1~16h;反应结束后,蒸干溶剂,残留物用硅胶柱层析进行纯化,得到R基团为的化合物I;
或者,
将摩尔比为1:1的化合物V和化合物IV依次加入DMF中,加入HBTU和DIPEA,在室温下搅拌反应1~16h;反应结束后,蒸干溶剂,残留物用硅胶柱层析进行纯化,得到化合物10;
或者,
将摩尔比为1:1.1的化合物V和非甾体抗炎药依次加入DMF中,加入HBTU和DIPEA,在室温下搅拌反应1~16h;反应结束后,蒸干溶剂,残留物用硅胶柱层析进行纯化,得到化合物9;
其中,化合物II的结构式如下:
化合物III的结构式如下:
化合物IV的结构式如下:
化合物V的结构式如下:
9.如权利要求8所述的含有p53-MDM2抑制剂的四价铂配合物的制备方法,其特征在于,所述酸酐为乙酸酐、三氟乙酸酐、正己酸酐、正辛酸酐、月桂酸酐、肉豆蔻酸酐、棕榈酸酐、油酸酐;
所述异氰酸酯为异氰酸己酯、异氰酸辛酯、异氰酸十二烷基酯。
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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CN112062791A (zh) * | 2020-09-28 | 2020-12-11 | 昆明贵研药业有限公司 | 一种基于顺铂的新型Pt(Ⅳ)配合物及其制备方法和用途 |
Non-Patent Citations (2)
Title |
---|
ATM Dependent DUSP6 Modulation of p53 Involved in Synergistic Targeting of MAPK and p53 Pathways with Trametinib and MDM2 Inhibitors in Cutaneous Melanoma;Chiao-En Wu et al.;《Cancers》;第11卷(第3期);第1-18页 * |
Oral idasanutlin in patients with polycythemia vera;Mascarenhas, John et al.;《blood》;第134卷(第6期);第495-496页 * |
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