CN114224883B - 一种β-连环蛋白特异性抑制剂的制药用途 - Google Patents

一种β-连环蛋白特异性抑制剂的制药用途 Download PDF

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CN114224883B
CN114224883B CN202111548623.9A CN202111548623A CN114224883B CN 114224883 B CN114224883 B CN 114224883B CN 202111548623 A CN202111548623 A CN 202111548623A CN 114224883 B CN114224883 B CN 114224883B
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龚惠
戴宇翔
葛均波
邹妍
黄晨兴
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Abstract

本发明提供了一种β‑连环蛋白特异性抑制剂在制备治疗心脏疾病药物中的用途，具体具有能够治疗扩张型心脏病、心肌纤维化等心脏疾病的作用。对于进一步开发相关治疗药物具有极大的临床意义。

Description

一种β-连环蛋白特异性抑制剂的制药用途
技术领域
本发明涉及医药技术领域，具体涉及一种β-连环蛋白特异性抑制剂的制药用途。
背景技术
扩张型心肌病(Dilated cardiomyopathy,DCM)是心力衰竭的第三大常见原因，是一种严重的心脏异质性病理疾病，其病理特征是以心室扩张为特征，并伴有收缩期和舒张期功能障碍。心肌纤维化(Myocardial fibrosis)是细胞外基质重构的病理实体，经常导致心肌硬度增加，DCM中既有反应性(间质和血管周)纤维化，也有修复性(替代性)纤维化，表明炎症和微血管损伤参与了疾病过程。在DCM患者中，心肌纤维化与不良预后和对治疗干预的反应受损有关。提示抗纤维化治疗可能有助于改善病变心脏的心功能。成纤维细胞被认为是心脏纤维化的主要细胞介质，在调节正常心功能和不良心肌重构中发挥重要作用。
Wnt基因同果蝇的体节极性基因无翅wingless(wg)同源，在人和小鼠，Wnt家族编码的19个高度保守的分泌信号分子，是调节细胞生长，分化以及细胞间相互作用的重要调节器。Wnt基因调控的重要信号传导系统即为Wnt通路，其中在经典的Wnt通路中，β-catenin活性的改变，胞浆蓄积，转导胞核激活通路下游靶基因，与调节细胞的生长、分化、增殖、凋亡以及胚胎发育尤为密切。在没有Wnt信号时，胞内游离的β-catenin被Axin和Apc识别后折叠使其磷酸化位点暴露，Cki把β-catenin的Ser45磷酸化后，Gsk3β磷酸化β-catenin的其他三个位点(Thr41，Ser37，Ser33)，β-catenin通过泛素化蛋白酶降解。当Wnt的配体出现时，与细胞膜上的Frizzled受体结合，Frizzled招募Dvl使得Cki不再去磷酸化β-catenin而去磷酸化Lrp5/6，致使β-catenin不被降解，通过核蛋白相互作用进入核内发挥作用。β-catenin高度保守的N-端区域(近130氨基酸)：包含Ser33,Ser37,Thr41,Ser45的磷酸化位点，使β-catenin翻译后保持稳定，且对调节转录活性非常重要，这个部位脱磷酸化的β-catenin称为Active-β-catenin。因此提示我们β-catenin抑制剂有可能能够用于治疗心肌纤维化。
β-catenin-IN-2是一种有效的β-catenin特异性抑制剂，该作用靶点主要是抑制β-catenin的活化，该化合物最早被报道于US20150374662A1用于治疗结肠癌的研究，2021年报道用于胃癌的研究，但是并未见将其用于治疗心脏类疾病。
发明内容
为克服现有技术中的缺陷，本发明通过如下技术方案实现：
本发明提供了一种β-连环蛋白特异性抑制剂在制备治疗心脏疾病药物中的用途，所述β-连环蛋白特异性抑制剂为β-catenin-IN-2，即4-(5-氟-1H-1,3-苯并二唑-2-基)-N,N-二甲基苯胺，其结构如式I所示：
Figure GDA0004184146500000021
进一步的，所述治疗心脏疾病包括治疗扩张型心肌病、心肌收缩或扩张减弱、心肌纤维化、心力衰竭或心律失常；
进一步的，所述治疗扩张型心肌病包括抑制心肌细胞凋亡。
附图说明
图1：扩心病小鼠给药前后心脏大小比较图
图2：扩张病小鼠给药前后心肌细胞凋亡情况比较图
图3：扩心病小鼠给药前后心肌收缩能力情况比较图
图4：扩心病小鼠给药前后心肌纤维化情况比较图
图5：扩心病小鼠给药前后心肌收缩、凋亡及纤维化分子水平情况比较图
有益效果
本发明通过分子水平、细胞水平以及组织水平实验均证明：
抑制β-catenin活化的特异性抑制剂β-catenin-IN-2可以有效抑制心肌细胞凋亡、提高心肌的扩张和收缩能力、抑制心肌纤维化，进一步抑制扩张性心肌病病程的发展，具有治疗扩张型心肌病的作用。
具体实施方式
下面结合附图和具体实施方式对本发明作进一步详细的说明。
β-catenin-IN-2，是一种有效的β-catenin抑制剂，β-catenin-2(10-40μM)以剂量依赖的方式抑制HCT116细胞β-catenin/Tcf-4的转录活性。该药物的化学名为：4-(5-氟-1H-1,3-苯并二唑-2-基)-N,N-二甲基苯胺，分子式为：C15H14FN3，分子量为：255.29，CAS登记号为：1458664-10-2，其结构如式I所示：
Figure GDA0004184146500000041
以下实施例中，小鼠由江苏集萃药康生物科技股份有限公司提供；β-catenin-IN-2购自MCE(MeDChemExpress)，货号为HY-136464；其余常规试剂均为市售。
实施例1扩心病小鼠给药前后心脏大小的比较
该实验为扩心病小鼠给药前后心脏大小的比较实验。图1为DSC2缺失造成的以右心室为主的扩张性心肌病小鼠模型。通过心超检测小鼠心脏大小，在小鼠心腔变大时，对小鼠进行给药干预。图1A表示扩心病小鼠-安慰剂组；图1B表示扩心病小鼠的β-catenin-IN-2给药组。通过多次实验发现，扩心病小鼠在对照组使用安慰剂腹腔注射后，表现出心脏明显的变大(图1A)，而β-catenin-IN-2给药组心脏不变(图1B)。
实施例2扩心病小鼠给药前后心肌凋亡的比较
该实验为扩心病小鼠给药前后心肌凋亡的比较。图2为DSC2缺失造成的以右心室为主的扩张性心肌病小鼠模型。通过Tunel对小鼠心肌细胞进行凋亡相关检测，在小鼠心腔变大时，对小鼠进行药物干预。其中图2A(WT组)、图2B(WT+IN-2组)、图2C(KO组)、图2D(KO+IN-2)组分别表示正常对照小鼠-安慰剂组、正常对照小鼠-给药组、扩心病小鼠-安慰剂组、扩心病小鼠-给药组。通过多次实验发现，扩心病小鼠在对照组使用安慰剂腹腔注射后，表现出心肌明显的凋亡增加，但是在扩心病小鼠腹腔注射β-catenin-IN-2后，凋亡的情况得到抑制。
实施例3扩心病小鼠给药前后心肌收缩能力的比较
该实验为扩心病小鼠给药前后心肌收缩能力的比较。图3为DSC2缺失造成的扩张性心肌病小鼠心肌细胞收缩能力的情况。图3A、3B、3C分别表示单个心肌细胞收缩时细胞长度、最大收缩速率以及最大舒张速率；且每幅图中WT组、KO组、KO+IN-2组分别表示正常小鼠-安慰剂组、扩心病小鼠-安慰剂组以及扩心病小鼠-给药组。通过对分离下来的KO小鼠心肌细胞单收缩实验发现，扩心病小鼠在使用安慰剂腹腔注射后，表现出心肌细胞收缩能力的下降，但是在扩心病小鼠腹腔注射β-catenin-IN-2后，分离下来的心肌细胞收缩能力得到回升。
实施例4扩心病小鼠给药前后心肌纤维化的比较
该实验为扩心病小鼠给药前后心肌纤维化的比较。图4为DSC2缺失造成的以右心室为主的扩张性心肌病小鼠模型。通过心超检测小鼠心脏大小，在小鼠心腔变大时，对小鼠进行药物干预。图4A、4B、4C、4D分别表示正常对照小鼠-安慰剂组、正常小鼠-给药组、扩心病小鼠-安慰剂组、扩心病小鼠-给药组。通过多次实验发现，扩心病小鼠在使用安慰剂腹腔注射后，表现出心脏明显的纤维化，但是在扩心病小鼠腹腔注射β-catenin-IN-2后，纤维化的症状得到抑制。
实施例5扩心病小鼠给药前后心肌收缩，凋亡及纤维化分子水平的比较
该实验为扩心病小鼠给药前后心肌纤维化及凋亡情况分子的比较。图5为DSC2缺失造成的以右心室为主的扩张性心肌病小鼠关于心肌收缩，凋亡纤维化的分子水平表达情况。通过Western Blot检测小鼠纤维化和凋亡水平，在小鼠心腔变大时，对小鼠进行药物干预。通过多次实验发现，扩心病小鼠使用安慰剂腹腔注射后，分子水平表现出心脏明显的纤维化和凋亡，但是在扩心病小鼠组腹腔注射β-catenin-IN-2后，凋亡，心肌收缩及纤维化的表现得到抑制。
以上详细描述了本发明的较佳具体实施例。应当理解，本领域的普通技术人员无需创造性劳动就可以根据本发明的构思做出诸多修改和变化。因此，凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验可以得到的技术方案，皆应在由权利要求书所确定的保护范围内。

Claims (2)

1.一种β-连环蛋白特异性抑制剂在制备治疗扩张型心肌病药物中的用途，其特征在于，所述β-连环蛋白特异性抑制剂为β-catenin-IN-2，即4-(5-氟-1H-1,3-苯并二唑-2-基)-N,N-二甲基苯胺，其结构如式I所示：
Figure FDA0004193834430000011
2.根据权利要求1所述的用途，其特征在于，所述治疗扩张型心肌病为抑制心肌细胞凋亡。
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