CN114010758A - Azd5582在制备治疗骨髓增生异常综合征药物中的应用 - Google Patents
Azd5582在制备治疗骨髓增生异常综合征药物中的应用 Download PDFInfo
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Abstract
本发明公开了AZD5582在制备治疗骨髓增生异常综合征药物中的应用，首次使用AZD5582处理骨髓增生异常综合征的细胞系，且AZD5582以低剂量显著抑制细胞系增殖和促进诱导细胞凋亡。本发明为临床研发新药用于治疗骨髓增生异常综合征提供了一种有效选择。
Description
技术领域
本发明涉及AZD5582的新用途，具体涉及AZD5582在制备治疗骨髓增生异常综合征药物中的应用。属于医药技术领域。
背景技术
骨髓增生异常综合征(myelodysplastic syndrome)是一种主要影响老年人群的异质性造血系统恶性肿瘤，包括一系列克隆性骨髓疾病，其特征为无效造血作用导致的外周血细胞减少和发育不良，以及发展为急性髓系白血病的可变风险，所以它的总体生存期较差。其临床上主要症状是感染、出血和严重的贫血。
骨髓增生异常综合征以成年人发病为主，常见于老年，男性发病多于女性。在美国，每年有3万到4万例确诊病例，确诊时的中位年龄约为70岁。在65岁以上的人群中，发病率为每10万人中有75例。它的发病原因尚未阐明，主要与含苯化合物的接触有一定的关系，也与现代污染的增加、工业的发展有关。
细胞凋亡(apoptosis)，亦称程序性细胞死亡(pro-grammed cell death)，指细胞在一定的生理或病理条件下，遵循自身的程序，由基因控制的主动的死亡过程。细胞凋亡是一种不同于坏死的死亡方式，是细胞内在的有规律的自我消亡。这种死亡没有溶酶体和细胞膜的破裂，没有细胞内容物外泄，而是细胞膜皱缩、内陷将细胞自行分割包被形成多个内含数目不等的细胞器凋亡小体，凋亡小体被吞噬细胞识别、吞噬或自然脱落而离开生物体，不引起炎症反应和次级损伤。研究发现，细胞凋亡与细胞的正常发育有关，而且使得损坏细胞或者机能紊乱细胞的自我毁损能够在一种可控的方式下进行。细胞凋亡中很多重要调节子都是潜在的癌基因，细胞凋亡失控会导致细胞内DNA受损，进而发展成为癌细胞。
细胞凋亡调控细胞生长和增殖之间的平衡，清除不需要的细胞，其凋亡机制作为可能的癌症治疗策略是目前研究的热点，与caspase基因家族、bcl-2基因家族密切相关。
AZD5582(L-Prolinamide,3,3'-[2,4-hexadiyne-1,6-diylbis[oxy[(1S,2R)-2,3-dihydro-1H-indene-2,1-diyl]]]bis[N-methyl-L-alanyl-(2S)-2-cyclohexylglycyl-)，二聚化SMACMIMETICS,IAPS抑制剂；(2S,2'S)-1,1'-((S,2S,2'S)-2,2'-(((1S,1'S,2R,2'R)-(己-2,4-二炔-Chemicalbook1,6-二基双(氧))双(2,3-二氢-1H-茚-2,1-二基))双(环己烷-3,1-二基))双(2-((S)-2-(甲胺基)丙胺基)乙酰基)双(吡咯烷-2-甲酰胺)，一种人工合成的新型的小分子IAP抑制剂，化学式为C58H78N8O8，其相对分子质量为1015.29，化学结构式如图1所示，与cIAP1、cIAP2和XIAP的BIR3区域有效结合，可诱导凋亡。在不同的癌症中，AZD5582所起的效果略有不同。不同的人胰腺癌细胞对IAP拮抗剂AZD5582具有不同的敏感性。AZD5582处理人胰癌细胞能不同程度地引起细胞凋亡，这取决于细胞系中p-Akt和p-XIAP的表达。它在胰腺癌中能够靶向cIAP1、诱导TNF-α引起的凋亡。它能引起Mcl-1蛋白(Bcl-2家族成员)的表达降低，而不影响Bcl-2和Bcl-xL。AZD5582还能引起头颈部鳞状细胞癌细胞系SCC25,Cal27和FaDu的剂量依赖式毒性作用。AZD5582处理不会带来广泛的细胞毒性，而在特定的肿瘤背景下，如对IAP抑制剂敏感的肿瘤或与其他靶向治疗有机结合时发挥毒性作用。AZD5582的二盐酸盐形成具有足够的水溶解度，能够配制成适用于静脉注射的溶液。至于AZD5582的化学稳定性，在pH4～6的环境下，AZD5582是不感光的，水解作用稳定。在强酸(pH<1)或强碱(pH>8)条件下，可能有一些酰胺水解。除此之外，AZD5582在多种物种的血浆中稳定。
目前尚无将AZD5582用于骨髓增生异常综合征治疗的相关报道。
发明内容
本发明的目的是为克服上述现有技术的不足，提供AZD5582在制备治疗骨髓增生异常综合征药物中的应用。
为实现上述目的，本发明采用下述技术方案：
1、AZD5582(C58H78N8O8)在制备治疗骨髓增生异常综合征药物中的应用。
2、一种治疗骨髓增生异常综合征的药物，其有效成分为AZD5582。
优选的，AZD5582的浓度为1～2μmol/L。
进一步优选的，AZD5582的浓度为2μmol/L。
本发明的有益效果：
本发明首次将一种小分子IAP抑制剂AZD5582用于骨髓增生异常综合征的治疗，具体来说，首次使用AZD5582处理骨髓增生异常综合征的细胞系，且AZD5582以低剂量显著抑制细胞系增殖和促进诱导细胞凋亡。本发明为临床研发新药用于治疗骨髓增生异常综合征提供了一种有效选择。
与现有技术相比，AZD5582能以低剂量显著抑制细胞增殖，且能诱导细胞发生凋亡。该用药大大提高了治疗骨髓增生异常综合征的效率，与常规的临床化疗药物相比，AZD5582副作用小，成本低，具有极大的发展前景和潜在价值。
附图说明
图1为AZD5582的化学结构式。
图2为本发明采用CCK-8法检测AZD5582对SKM-1细胞(A)、MDS-L细胞(B)存活率的影响。SKM-1、MDS-L是人类骨髓增生异常综合征细胞系。*P<0.05，**P<0.01，***P<0.001。
图3为本发明采用Annexin V/PI双染色法流式检测AZD5582处理SKM-1、MDS-L细胞后对凋亡的诱导作用。
具体实施方式
下面结合附图和实施例对本发明进行进一步的阐述，应该说明的是，下述说明仅是为了解释本发明，并不对其内容进行限定。
本发明涉及的AZD5582，购自Selleck公司。
实施例1
采用CCK-8方法检测AZD5582对SKM-1、MDS-L细胞存活率的影响
实验步骤：
(1)收集对数生长期的SKM-1、MDS-L细胞(由天津血液学研究所赠送)，调整细胞悬液浓度，每孔加入100μL，96孔板铺板，使待测细胞密度为1*105个/mL；
(2)设置不加细胞只有培基(体积百分数10％胎牛血清(购自BI)+体积百分数90％1640培养基(购自Gibco))的凋零组以及不加药物只加细胞的NC组，每个浓度设置3-5个平行孔；
(3)分别加入1μmol/L和2μmol/L AZD5582(购自selleck)，置于体积百分数5％CO2，37℃细胞培养箱中孵育24小时；
(4)每孔加入10μL CCK-8溶液(购自Bimake)，置于37℃条件下避光孵育2小时，用酶标仪在450nm波长处测量各孔的OD值，进行统计学分析，计算细胞相对存活率。
实验结果如图2所示，结果表明，AZD5582在2μmol/L的浓度时对细胞抑制作用很强(图2中A、B分别为AZD5582对SKM-1细胞、MDS-L细胞的存活率影响)，统计学分析具有显著性差异。
实施例2
采用Annexin V/PI方法检测AZD5582处理SKM-1、MDS-L细胞后对凋亡的诱导作用
实验步骤：
(1)收集对数生长期的SKM-1、MDS-L细胞，调整细胞悬液浓度为5*105个/mL于6孔板中，总体积为2ml，然后分别加入0μmol/L、1μmol/L和2μmol/L AZD5582，以不加药物处理组为对照，置于细胞培养箱中孵育24小时。
(2)收集细胞，300g，4℃离心5分钟收集细胞，用预冷的DPBS(购自Gibco)洗涤细胞两次，每次均在300g，4℃离心5分钟。收集1-5*105个细胞。
(3)加入100μL 1×Binding Buffer(购自ZETA LIFE)重悬细胞。
(4)加入5μL Annexin V-FITV(购自ZETA LIFE)和5μL PI Staining Solution(购自ZETA LIFE)，轻轻混匀。
(5)避光，室温反应10分钟。
(6)加入400μL DPBS，轻轻混匀。并将其转移至流式管中。用流式细胞仪检测凋亡情况。
实验结果如图3所示，结果表明，AZD5582能显著诱导细胞凋亡，但是对不同的细胞，同样的药物浓度诱导细胞凋亡的比率不同。
上述虽然结合附图对本发明的具体实施方式进行了描述，但并非对本发明保护范围的限制，在本发明的技术方案的基础上，本领域技术人员不需要付出创造性劳动即可做出的各种修改或变形仍在本发明的保护范围以内。
Claims (3)
1.AZD5582在制备治疗骨髓增生异常综合征药物中的应用。
2.一种治疗骨髓增生异常综合征的药物，其特征在于，其有效成分为AZD5582。
3.根据权利要求2所述的一种治疗骨髓增生异常综合征的药物，其特征在于，AZD5582的浓度为1～2μmol/L。
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| MARI HASHIMOTO等: ""Combined inhibition of XIAP and BCL2 drives maximal therapeutic efficacy in genetically diverse aggressive acute myeloid leukemia"", 《NATURE CANCER》 * |
| NOELLE V. FREY等: ""A Phase I Study Using Single Agent Birinapant in Patients with Relapsed Myelodysplastic Syndrome and Acute Myelogenous Leukemia"", 《BLOOD》 * |
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