CN115887457A - 小分子化合物和来那度胺在制备治疗多发性骨髓瘤药物中的应用 - Google Patents
小分子化合物和来那度胺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来那度胺在制备治疗多发性骨髓瘤药物中的应用。如何促进下游底物即骨髓瘤细胞增殖必须的转录因子IKZF1的降解，是多发性骨髓瘤疾病治疗中的难点。本发明使用小分子化合物2‑BP和来那度胺联用，在多发性骨髓瘤治疗中的作用，能够显著降低IKZF1蛋白水平，联合来那度胺处理多发性骨髓瘤细胞后，抑制多发性骨髓瘤细胞增殖。
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来那度胺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)是浆细胞恶化而形成的一种血液癌症。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。
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。
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。
来那度胺(Lenalidomide，Len)等免疫调节药物的上市，极大地延长了多发性骨髓瘤病人的生存期。
来那度胺是沙利度胺的类似物，具有免疫调节、抗血管生成和抗肿瘤的作用。来那度胺的细胞活性是由其靶蛋白cereblon介导的。体外试验中，在药物存在时，底物蛋白被靶向泛素化后降解，从而导致直接细胞毒作用和免疫调节作用。来那度胺在体外对某些造血系统肿瘤细胞(包括多发性骨髓瘤、套细胞淋巴瘤等具有抑制增殖和促进凋亡的作用。来那度胺在体内可延缓某些非临床血液肿瘤模型(包括多发性骨髓瘤)的肿瘤生长。来那度胺的免疫调节作用包括：增加T细胞和自然杀伤细胞的数量和活性，通过IL-2和INF-γ分泌的增加、自然杀伤T细胞数量的增加、抑制单核细胞的促炎性细胞因子释放而直接增强抗体依赖性细胞介导的细胞毒作用(ADCC)。来那度胺和地塞米松联用可协同抑制多发性骨髓瘤细胞的增殖并诱导细胞凋亡。在体外试验中，与利妥昔单药相比，来那度胺和利妥昔单抗联用可增强对滤泡性淋巴瘤细胞的ADCC作用，并导致肿瘤细胞直接凋亡，可增强对边缘区淋巴瘤细胞的ADCC作用。
然而，单一药物的耐药性，仍然限制着这类药物的应用。来那度胺是通过其结合蛋白cereblon(CRBN)来降解下游底物IKZF1，而IKZF1是骨髓瘤细胞增殖所必需的转录因子，因此来那度胺通过CRBN-IKZF1进而抑制多发性骨髓瘤细胞增殖，从而达到治疗多发性骨髓瘤疾病的目的。
来那度胺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，基于来那度胺的联合用药，成为了治疗多发性骨髓瘤的首选。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。
多发性骨髓瘤病人长期使用来那度胺治疗后，体内CRBN蛋白水平下降，使得病人对来那度胺出现耐受。如何促进下游底物即骨髓瘤细胞增殖必须的转录因子IKZF1的降解，是多发性骨髓瘤疾病治疗中的难点。
发明内容
为了解决现有技术存在的问题，本发明提供小分子化合物和来那度胺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2-BP(2-溴棕榈酸，2-bromopalmitate，CAS：18263-25-7)。
优选的，所述药物用于降低IKZF1蛋白水平。
优选的，所述药物用于提高多发性骨髓瘤细胞对来那度胺的敏感性。
本发明还提供一种预防和/或治疗多发性骨髓瘤的药物，包括上述的小分子化合物2-BP和来那度胺。
进一步地，所述药物还包括药学上可接受的载体。
具体的，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。
具体的，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。
药片中最常见的添加剂为玉米淀粉，口服片剂中加入的玉米淀粉是一种填充剂，也叫稀释剂，主要作用是增加药物的重量或体积，以便于将药物压成片剂。
一般对片剂的要求是：直径不能小于6毫米，重量在100毫克以上。如果片剂中的主药只有几毫克或几十毫克，将无法制成片剂。此时，可通过加入适当的填充剂来增加体积，让药片够分量，助其成型。除了玉米淀粉外，常用的填充剂还有糖类、糊精、甘露醇等。一种药片中往往含有多种填充剂，比如玉米淀粉常与可压性较好的糖粉、糊精混合使用；这是因为淀粉的可压性较差，若单独使用，会使压出的药片过于松散。
填充剂，比如甘露醇，在口中溶解时吸热，有凉爽感，能够用来制备咀嚼片，可与蔗糖配合使用。
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。
口服是最主要的用药方式，药物可以经过口服后消化道吸收的药物。小肠黏膜表面的面积非常大，药物一般是在小肠中被吸收。只有少部分的药物可以通过胃来吸收，通常都是一些酸性的药物。
如果不能通过口服或者消化道给药，就会选择外给药的方式。
很多昏迷和呕吐不止的患者，不能口服，还有一些药物在消化道吸收不良，而且容易被各种因素破坏，这种情况下我们就考虑用注射的方法给药。有两种主要的方式，一种是在肌肉内注射，也就是打肌肉针，另一种就是比较常见的滴注，也就是静脉注射。总体而言，肌内注射的首要条件就是这个药物必须是高度的水溶性。能够溶解在肌肉间质的液体中，导致这种药物可以被迅速地吸收。通常来说注射的部位是臀大肌或者肩部的三角肌。
要注意的是肌内注射对休克患者有弊端，这些患者的皮下和肌肉的血流量都非常少，局部肌肉内注射药物之后吸收量就很少了，此时考虑静脉给药。
本发明的技术方案相比现有技术具有以下优点：
如何促进下游底物即骨髓瘤细胞增殖必须的转录因子IKZF1的降解，是多发性骨髓瘤疾病治疗中的难点。本发明使用小分子化合物2-BP和来那度胺联用，在多发性骨髓瘤治疗中的作用。能够显著降低IKZF1蛋白水平，联合来那度胺处理多发性骨髓瘤细胞后，抑制多发性骨髓瘤细胞增殖。
附图说明
图1为免疫印迹法检测IKZF1的蛋白水平变化图。
图2为来那度胺抑制多发性骨髓瘤细胞增殖作用图。
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
实施例1使用小分子化合物2-BP(购于Selleck)联合来那度胺(Len，购于MedChemExpress)处理多发性骨髓瘤细胞，来降低IKZF1蛋白量。
取市购所得RPMI8226和LP1细胞铺24孔板，用2-BP(10μM)预处理RPMI8226、LP1细胞1h后，用来那度胺(10μM)处理12h，接着收细胞裂解，用免疫印迹法检测IKZF1的蛋白水平变化。
该免疫印迹蛋白的检测方法，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(pH7.4)、1mM EDTA、Protein inhibitors(Bimake))裂解后，超声破碎，添加5×SDS-PAGE loading buffer上样缓冲液(250mM Tris-HCL(pH6.8)、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Tanon5200仪器采集图片。
由图1可以看出，2-BP联合来那度胺能够显著下调IKZF1蛋白水平。
实施例2
实施例2是为了验证小分子化合物2-BP能够显著提高来那度胺抑制多发性骨髓瘤细胞增殖的作用。
使用RPMI8226骨髓瘤细胞铺24孔板，加入2-BP(10μM)预处理1h后，LEN(10μM)处理5天，使用细胞增殖活性试剂盒CCK8(购于碧云天生物技术)检测细胞增殖情况。
Cell Counting Kit8简称CCK-8试剂盒，是用于测定细胞增殖或毒性实验中活细胞数目的一种高灵敏度，无放射性的比色检测法。
CCK-8属于MTT的升级产品，CCK-8溶液可以直接加入到细胞样品中，不需要预配各种成分，可以检测快速，毒性低。CCK-8基于水溶性四唑盐WST-8。工作原理为：WST-8在电子耦合试剂存在的情况下，可以被线粒体内的脱氢酶还原生成橙黄色的甲臜染料。甲臜染料能够溶解在组织培养基中，与活细胞数量成正比。通过比色，可以动态地量化活细胞的数量，从而对细胞增殖或药物毒性进行检测本试剂盒通常用于贴壁或悬浮细胞的周期与凋亡检测。如果用于组织，则需要把组织消化成单细胞状态，再可以进行检测。
图2中可以看出，使用小分子化合物2-BP联合LEN能够显著抑制骨髓瘤细胞增殖。
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.小分子化合物和来那度胺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2-BP。
2.如权利要求1所述的应用，其特征在于，所述药物用于降低IKZF1蛋白水平。
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来那度胺的敏感性。
4.一种预防和/或治疗多发性骨髓瘤的药物，其特征在于，包括权利要求1所述的小分子化合物和来那度胺。
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、膏剂和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1-100mg/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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