CN114869897B - 小分子化合物和硼替佐米在制备治疗多发性骨髓瘤药物中的应用 - Google Patents
小分子化合物和硼替佐米在制备治疗多发性骨髓瘤药物中的应用 Download PDFInfo
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Abstract
本发明属于医药领域，具体涉及小分子化合物和硼替佐米在制备治疗多发性骨髓瘤药物中的应用。硼替佐米治疗多发性骨髓瘤具有很好的效果，然而单一药物的耐药性，仍然限制着这类药物的应用，本发明在此基础上，通过添加小分子抑制剂IRAK‑1‑4抑制剂I和HS‑243在抑制多发性骨髓瘤细胞增殖，与硼替佐米进行联合用药，提高了多发性骨髓瘤细胞对硼替佐米敏感性，提高了治疗效果。
Description
技术领域
本发明属于医药领域，具体涉及小分子化合物和硼替佐米在制备治疗多发性骨髓瘤药物中的应用。
背景技术
多发性骨髓瘤(MM)是一种恶性浆细胞病，是浆细胞恶化而形成的一种血液癌症。其肿瘤细胞起源于骨髓中的浆细胞，而浆细胞是B淋巴细胞发育到最终功能阶段的细胞。因此多发性骨髓瘤可以归到B淋巴细胞淋巴瘤的范围。目前将其归为B细胞淋巴瘤的一种，称为浆细胞骨髓瘤/浆细胞瘤。其特征为骨髓浆细胞异常增生伴有单克隆免疫球蛋白或轻链(M蛋白)过度生成，极少数患者可以是不产生M蛋白的未分泌型多发性骨髓瘤。多发性骨髓瘤常伴有多发性溶骨性损害、高钙血症、贫血、肾脏损害。由于正常免疫球蛋白的生成受抑，因此容易出现各种细菌性感染。发病率估计为2～3/10万，男女比例为1.6：1，大多患者年龄>40岁。
多发性骨髓瘤起病缓慢，早期无明显症状。多发性骨髓瘤的临床表现多样，主要有贫血、骨痛、肾功能不全、感染、出血、神经症状、高钙血症、淀粉样变等。骨痛、骨骼变形和病理骨折，骨髓瘤细胞分泌破骨细胞活性因子而激活破骨细胞，使骨质溶解、破坏，骨骼疼痛是最常见的症状，多为腰骶、胸骨、肋骨疼痛。由于瘤细胞对骨质破坏，引起病理性骨折，可多处骨折同时存在。贫血和出血，贫血较常见，为首发症状，早期贫血轻，后期贫血严重。晚期可出现血小板减少，引起出血症状。皮肤黏膜出血较多见，严重者可见内脏及颅内出血。肝、脾、淋巴结和肾脏病变，肝、脾肿大，颈部淋巴结肿大，骨髓瘤肾。器官肿大或者异常肿物需要考虑髓外浆细胞瘤或者淀粉样变。
神经系统症状，神经系统髓外浆细胞瘤可出现肢体瘫痪、嗜睡、昏迷、复视、失明、视力减退。多发性骨髓瘤多见细菌感染，亦可见真菌、病毒感染，最常见为细菌性肺炎、泌尿系感染、败血症，病毒性带状庖疹也容易发生，尤其是治疗后免疫低下的患者。肾功能损害，50％～70％患者尿检有蛋白、红细胞、白细胞、管型，出现慢性肾功能衰竭、高磷酸血症、高钙血症、高尿酸血症，可形成尿酸结石。多发性骨髓瘤的耐药和易复发等特征，使这类疾病仍然难以治愈。
硼替佐米(Bortezomib，Btz)等蛋白酶体抑制剂药物的上市，极大地延长了多发性骨髓瘤病人的生存期。然而，单一药物的耐药性，仍然限制着这类药物的应用。联合用药是目前治疗多发性骨髓瘤疾病的最主要策略。
硼替佐米(Bortezomib，Btz)是哺乳动物细胞中26S蛋白酶体糜蛋白酶样活性的可逆抑制剂。体外试验证明硼替佐米对多种类型的癌细胞具有细胞毒性。临床前肿瘤模型体内试验证明硼替佐米能够延迟包括多发性骨髓瘤在内的肿瘤生长。本品用于多发性骨髓瘤患者的治疗，有效性基于它的有效率。
硼替佐米是哺乳动物细胞中26S蛋白酶体糜蛋白酶样活性的可逆抑制剂。26S蛋白酶体是一种大的蛋白质复合体，可降解泛蛋白。泛蛋白酶体通道在调节特异蛋白在细胞内浓度中起到重要作用，以维持细胞内环境的稳定。蛋白水解会影响细胞内多级信号串联，这种对正常的细胞内环境的破坏会导致细胞的死亡。而对26S蛋白酶体的抑制可防止特异蛋白的水解。体外试验证明硼替佐米对多种类型的癌细胞具有细胞毒性。临床前肿瘤模型体内试验证明硼替佐米能够延迟包括多发性骨髓瘤在内的肿瘤生长。
硼替佐米用于多发性骨髓瘤患者的治疗，此患者在使用本品前至少接受过两种治疗，并在最近—次治疗中病情还在进展。硼替佐米的有效性基于它的有效率。尚无临床对照试验证明其临床利益，如对存活率的改善。
在临床研究中，被确认完全有效的患者再接受另外2个周期的注射用硼替佐米治疗。建议有效的患者接受8个周期的注射用硼替佐米治疗。
硼替佐米治疗多发性骨髓瘤具有很好的效果，然而单一药物的耐药性，仍然限制着这类药物的应用。近些年来，基于硼替佐米的联合用药，成为了治疗多发性骨髓瘤的重要策略。然而，这类疾病易复发和耐药性出现，使得开发新的联合用药机制和策略成为了治疗该类疾病的难度和热点。
IL-1受体相关激酶在信号转导中起重要作用。IRAKs一共有4个成员，分别为IRAK-1、IRAK-2、IRAK-M和IRAK-4。IRAK-4可以激活NF-KB和MAPK途径，IRAK-4的抑制可用于抗炎治疗。
IRAK-1-4Inhibitor 1是初始IRAK-4抑制剂命中的类似物，初始IRAK-4抑制剂是从抑制IRAK-4的小分子库中筛选到的。IRAK-1-4抑制剂I具有碱性较弱的N-ethylenemorpholine部分，比其它类似物具有更高的效力。此外，在Hela细胞72小时增殖实验中，IRAK-1-4Inhibitor 1不具有任何细胞毒性(ED50>30μM)。
发明内容
为解决以上技术问题，本发明公开了小分子抑制剂IRAK-1-4抑制剂I和HS-243在抑制多发性骨髓瘤细胞增殖，并且能够联合硼替佐米用药，进而提高了多发性骨髓瘤细胞对硼替佐米敏感性的新应用。
本发明提供小分子化合物和硼替佐米在制备治疗多发性骨髓瘤药物中的应用，所述小分子化合物为IRAK-1-4抑制剂I和化合物HS-243；
优选的，所述IRAK-1-4抑制剂I是IRAK-1和IRAK-4的抑制剂，IC50值分别为0.3μM和0.2μM，其化学结构如下：
优选的，所述化合物HS-243，CAS号为848249-10-5，其化学结构如下：
优选的，所述药物用于抑制多发性骨髓瘤细胞增殖。
优选的，所述药物用于提高多发性骨髓瘤细胞对硼替佐米的敏感性。
本发明还提供一种预防和/或治疗急性移植物抗宿主病的药物，包括权利要求1所述的小分子化合物和硼替佐米。
进一步地，所述药物还包括药学上可接受的载体。
进一步地，所述载体选自片剂、胶囊剂、丸剂、粉末剂、栓剂、膏剂及溶液剂和悬浮剂的一种或多种。
进一步地，所述药物还包括添加剂。
进一步地，所述添加剂为抗氧化剂、防腐剂、增溶剂、崩解剂、润滑剂、着色剂、分散剂和表面活性剂中的一种或多种。
进一步地，所述药物的给药剂量为1-100mg/kg。
进一步地，所述药物的给药方式为口服、腹腔注射、皮下注射、静脉注射和肌肉注射中的一种或多种。
本发明的技术方案相比现有技术具有以下优点：
硼替佐米治疗多发性骨髓瘤具有很好的效果，然而单一药物的耐药性，仍然限制着这类药物的应用，本发明在此基础上，通过添加小分子抑制剂IRAK-1-4抑制剂I和HS-243在抑制多发性骨髓瘤细胞增殖，与硼替佐米进行联合用药，提高了多发性骨髓瘤细胞对硼替佐米敏感性，提高了治疗效果。
附图说明
图1为实施例1中免疫印迹法检测抑制多发性骨髓瘤细胞增殖数据对比图。
图2为实施例2中免疫印迹法检测抑制多发性骨髓瘤细胞增殖数据对比图。
具体实施方式
下面结合附图和具体实施例对本发明作进一步说明，以使本领域的技术人员可以更好地理解本发明并能予以实施，但所举实施例不作为对本发明的限定。
实施例1
小分子化合物IRAK-1-4抑制剂I(购于Selleck)和HS-243(购于Selleck)处理多发性骨髓瘤细胞，抑制其增殖，但是不影响其凋亡。
用IRAK-1-4抑制剂I(20μM)和HS-243(20μM)处理LP1、U266细胞，DMSO做对照组，24h后收细胞，用免疫印迹法检测凋亡蛋白PARP1的切割。
免疫印迹蛋白检测方法，具体方法如下：细胞使用RIPA裂解液(150mM Nacl、1％Triton x-100、0.1％SDS、50mM Tris-base(pH 7.4)、1mM EDTA、Protein inhibitors(Bimake))裂解后，超声破碎，添加5×SDS-PAGE loadingbuffer上样缓冲液(250mM Tris-HCL(pH 6.8)、10％SDS、0.25％溴酚蓝(BPB)、50％甘油、5％β-巯基乙醇)，98℃处理5-10min。利用10％蛋白胶进行SDS-PAGE实验，分离蛋白。转膜后，利用10％脱脂牛奶(3g脱脂奶粉、30ml 1xTBST缓冲液)封闭1h，接着孵育相应一抗和二抗。最后采用凝胶成像系统Tanon 5200仪器采集图片。
可以看出，IRAK-1-4抑制剂I和HS-243不影响多发性骨髓瘤细胞凋亡(图1)。另外，LP1和U266细胞在使用IRAK-1-4抑制剂I和HS-243(20μM)处理6天后，CCK8(购于碧云天生物技术)增殖检测试剂盒测量细胞增殖，结果发现IRAK-1-4抑制剂I和HS-243显著抑制多发性骨髓瘤细胞增殖(图1)。
实施例2
小分子化合物IRAK-1-4抑制剂I和HS-243增加硼替佐米(Bortezomib，Btz)(购于Selleck)敏感性。
使用DMSO、IRAK-1-4抑制剂I(20μM)、HS-243(20μM)和/或Btz(0.1μM)处理LP1细胞，24h后收细胞裂解，用免疫印迹法检测凋亡蛋白PARP1的切割。
免疫印迹蛋白检测方法，具体方法如下：细胞使用RIPA裂解液(150mM Nacl、1％Triton x-100、0.1％SDS、50mM Tris-base(pH 7.4)、1mM EDTA、Protein inhibitors(Bimake))裂解后，超声破碎，添加5×SDS-PAGE loadingbuffer上样缓冲液(250mM Tris-HCL(pH 6.8)、10％SDS、0.25％溴酚蓝(BPB)、50％甘油、5％β-巯基乙醇)，98℃处理5-10min。利用10％蛋白胶进行SDS-PAGE实验，分离蛋白。转膜后，利用10％脱脂牛奶(3g脱脂奶粉、30ml 1xTBST缓冲液)封闭1h，接着孵育相应一抗和二抗。最后采用凝胶成像系统Tanon 5200仪器采集图片。
可以看出，联合IRAK-1-4抑制剂I(Inhibitor I)、HS-243和Btz不影响PARP1的切割(图2)。另外，LP1细胞用DMSO、IRAK-1-4抑制剂I(20μM)、HS-243(20μM)和/或Btz(40nM)处理6天后，CCK8(购于碧云天生物技术)增殖检测试剂盒测量细胞增殖，结果发现联合IRAK-1-4抑制剂I(Inhibitor I)、HS-243和Btz能够显著抑制多发性骨髓瘤细胞增殖(图2)。这些结果说明，IRAK-1-4抑制剂I和HS-243能够增加多发性骨髓瘤细胞硼替佐米敏感性。
显然，上述实施例仅仅是为清楚地说明所作的举例，并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引申出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (10)
1.小分子化合物和硼替佐米在制备治疗多发性骨髓瘤药物中的应用，其特征在于，所述小分子化合物为IRAK-1-4抑制剂I和化合物HS-243，所述IRAK-1-4抑制剂I的化学结构如下：
。
2.如权利要求1所述的应用，其特征在于，所述药物用于抑制多发性骨髓瘤细胞增殖。
3.如权利要求1所述的应用，其特征在于，所述药物用于提高多发性骨髓瘤细胞对硼替佐米的敏感性。
4.一种预防和/或治疗急性移植物抗宿主病的药物，其特征在于，包括权利要求1所述的小分子化合物和硼替佐米。
5.根据权利要求4所述的药物，其特征在于，所述药物还包括药学上可接受的载体。
6.根据权利要求5所述的药物，其特征在于，所述载体选自片剂、胶囊剂、丸剂、粉末剂、栓剂、膏剂及溶液剂和悬浮剂的一种或多种。
7.根据权利要求4所述的药物，其特征在于，所述药物还包括添加剂。
8.根据权利要求7所述的药物，其特征在于，所述添加剂为抗氧化剂、防腐剂、增溶剂、崩解剂、润滑剂、着色剂、分散剂和表面活性剂中的一种或多种。
9.根据权利要求4所述的药物，其特征在于，所述药物的给药剂量为1-100 mg/kg。
10.根据权利要求4所述的药物，其特征在于，所述药物的给药方式为口服、腹腔注射、皮下注射、静脉注射和肌肉注射中的一种或多种。
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