CN115768744A - 作为ubr盒结构域配体的化合物 - Google Patents

作为ubr盒结构域配体的化合物 Download PDF

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CN115768744A
CN115768744A CN202180044509.4A CN202180044509A CN115768744A CN 115768744 A CN115768744 A CN 115768744A CN 202180044509 A CN202180044509 A CN 202180044509A CN 115768744 A CN115768744 A CN 115768744A
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ubr
muscular dystrophy
domain
compound
protein
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权容兑
金昡兑
罗贞恩
徐裕珍
池昌勋
崔荷琳
李知垠
许雅贞
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Austria Chooses To Break Through Wisdom
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Austria Chooses To Break Through Wisdom
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Abstract

本说明书涉及一种作为UBR盒结构域配体的化合物。本说明书提供了一种与UBR盒结构域结合的小分子量化合物。此外，本说明书提供了一种用于抑制UBR盒结构域底物结合的组合物、用于治疗UBR相关疾病的药物组合物及其用途，所述组合物包含与UBR盒结构域结合的配体化合物。

Description

作为UBR盒结构域配体的化合物
相关申请的交叉引用
本申请要求2020年4月27日提交的美国临时专利申请序列No.63/015,945的权益和优先权，通过引用的方式将其公开内容整体并入本文。
技术领域
本说明书中公开的内容涉及作为UBR盒结构域(UBR box domain)配体的化合物。UBR盒结构域是N-端规则途径(N-end rule pathway)的泛素蛋白连接酶E3成分n-识别蛋白(Ubiquitin protein ligase E3 component n-recognin，UBR)蛋白质中普遍存在的结构域。在此情况下，UBR盒结构域被称为底物结合的结构域。UBR盒结构域对于与底物的N-末端残基结合以在底物中形成多泛素链而言是必不可少的，并且已知底物会通过该过程被降解。
本说明书涉及用作与UBR盒结构域结合的配体的化合物。
背景技术
细胞通过降解蛋白质来调节体内蛋白质的数量和功能。在此情况下，体内蛋白质可以根据N-末端残基序列而被降解，这种降解途径被称为N-端规则途径(N-end rulepathway)。即，N-端规则途径是一种使用特定的蛋白质N-端作为降解信号的蛋白水解***。N-端规则途径可以包括以下蛋白水解过程。
在真核生物的情况下，N-识别蛋白(N-recognin)对蛋白质的N-末端降解信号进行识别，并且N-识别蛋白可以通过使泛素与待降解的蛋白质结合来降解蛋白质。在此情况下，N-末端降解信号可以包括在N-末端具有带正电荷的残基(1型：例如，精氨酸、赖氨酸和组氨酸)或大的疏水残基(2型：苯丙氨酸、亮氨酸、色氨酸、异亮氨酸和酪氨酸)的那些N-末端降解信号。本发明人首次发现或克隆了N-识别蛋白UBR1、UBR2、UBR3和UBR5，并揭示了N-识别蛋白具有UBR盒结构域作为底物识别结构域(Tasaki等人，2005)。在此情况下，由N-识别蛋白与N-端规则配体的结合产生的泛素化底物被递送至蛋白酶体并被降解成短肽。在此过程中，当N-识别蛋白靶向N-端规则底物时，特定的N-末端残基(Nt-Arg、Nt-His、Nt-Lys、Nt-Trp、Nt-Phe、Nt-Tyr、Nt-Leu、Nt-Leu)提供了所需的大部分氢键，因此特定的N-末端残基是结合所必需的决定因素(Sriram和Kwon，2010)。
UBR是泛素蛋白连接酶E3成分n-识别蛋白的缩写，并且UBR是一种识别蛋白质的N-末端降解信号的N-识别蛋白。已知在哺乳动物中存在UBR1至UBR7至少7种类型。此外，UBR共有的UBR盒结构域是具有大小约为70个残基的锌指基序，并且被称为高度保守的底物结合结构域。[Kwon等人，1998；Xie和Varshavsky，1999；Kwak等人，2004；Varshavsky，1996；Varshavsky，1997；Kwon等人，2011；以及Zenker等人，2014]。
即，UBR是一种与N-端规则途径相关的N-识别蛋白，N-端规则途径是一种蛋白水解途径，并且UBR中的UBR盒结构域是底物结合结构域。特别地，在UBR1至UBR7中，已知UBR1、UBR2、UBR3和UBR5充当泛素蛋白连接酶E3并具有RING结构域或HECT结构域。与UBR结合的N-端规则底物通过泛素蛋白酶体途径被降解。具体而言，UBR中的UBR盒结构域识别底物的N-末端氨基酸，并经由RING结构域或HECT结构域使底物泛素化，从而经由蛋白酶体途径降解底物。例如，当错误折叠的蛋白质在细胞中停留较长时间时，蛋白质可能会聚集以阻断蛋白酶体或降低其他细胞功能，从而经由泛素蛋白酶体途径被降解(Ji和Kwon，2017)。
即，UBR盒结构域通过识别N-末端降解信号在细胞内蛋白水解途径中发挥重要作用。因此，与UBR盒结构域结合的配体可能会影响细胞内蛋白水解途径。
如上所述，本说明书涉及作为与UBR盒结构域结合的配体的化合物，所述UBR盒结构域与细胞内蛋白水解途径相关。
发明内容
技术问题
本说明书提供了与UBR盒结构域结合的小分子化合物。在此情况下，UBR盒结构域包括UBR1至UBR7中的UBR盒结构域。所述小分子化合物能够作为适合与UBR盒结构域结合的配体起作用。
在一个实施方式中，本说明书提供了一种用于抑制UBR盒结构域底物结合的组合物，所述组合物包含与UBR盒结构域结合的配体化合物。
在一个具体的实施方式中，本说明书提供了一种用于治疗UBR相关疾病的药物组合物及其用途，所述组合物包含与UBR盒结构域结合的配体化合物。
在更具体的实施方式中，本说明书提供了一种用于治疗下述疾病的药物组合物及其用途，所述组合物包含与UBR盒结构域结合的配体化合物，所述疾病包括：由肌肉营养不良(muscular dystrophy)(贝克型肌营养不良(Becker)、先天性肌营养不良(Congennital)、杜兴氏肌营养不良(Duchenne)、远端型肌营养不良(Distal)、埃-德型肌营养不良(Emery-Dreifuss)、面肩肱型肌营养不良(Facioscapulohumeral)、肢带型肌营养不良(Limb-girdle)、强直性肌营养不良(myotonic)、眼咽肌营养不良(ocuophargyngeal))引起的肌肉损失；由肌肉损失或退化介导的肌肉萎缩疾病，包括少肌症或癌症恶病质；由蛋白质过度降解引起的疾病，包括脂肪肉瘤、囊性纤维化、Johanson-Blizzard综合征、梗阻性尿路疾病(尿道阻塞序列征(urethral obstruction sequence))、自身免疫性胰腺炎；或与UBR盒和UBR蛋白相关的已知疾病，包括Usher综合征。
技术方案
本说明书提供了一种具有式1结构的化合物或其盐。
[式1]
Figure BDA0004011798420000031
其中，A1为CH3或NH2。
在此情况下，作为实例，本说明书提供了一种用于抑制UBR盒结构域底物结合的组合物，所述组合物包含其中A1为CH3或NH2的化合物或其盐。
在此情况下，作为实例，本说明书提供了一种用于治疗UBR相关疾病的药物组合物，所述药物组合物包含其中A1为CH3或NH2的化合物或其药学上可接受的盐，并且还提供了通过使用所述化合物用于治疗UBR相关疾病的方法。
在此情况下，作为实例，UBR相关疾病可以选自：由肌肉营养不良(贝克型肌营养不良、先天性肌营养不良、杜兴氏肌营养不良、远端型肌营养不良、埃-德型肌营养不良、面肩肱型肌营养不良、肢带型肌营养不良、强直性肌营养不良、眼咽肌营养不良)引起的肌肉损失；由肌肉损失或退化介导的肌肉萎缩疾病，包括少肌症或癌症恶病质；由蛋白质过度降解引起的疾病，包括脂肪肉瘤、囊性纤维化、Johanson-Blizzard综合征、梗阻性尿路疾病(尿道阻塞序列征)、自身免疫性胰腺炎；或Usher综合征。
有益效果
本文公开的发明提供了相对于UBR盒结构域具有高结合强度的配体化合物。
通过UBR盒结构域配体化合物，能够抑制UBR盒结构域底物结合，并且能够提供利用该特性的各种应用。例如，UBR相关疾病(例如，肌肉损失等)能够通过UBR盒结构域配体化合物进行治疗。
附图说明
图1说明了使用免疫印迹法确认肌动蛋白是否是Arg/N-degron途径底物的实验结果。
图2说明了使用体外转录/翻译方法确认R-nsp4是否根据化合物(化合物1、化合物2)与UBR1的结合而表达的实验结果。
图3说明了使用免疫印迹法确认化合物(化合物1、化合物2)是否抑制肌细胞中的肌动蛋白的降解的实验结果。
图4和图5说明了通过微量热泳(microscale thermophoresis，MST)测量化合物1和化合物2的结合的结果。
具体实施方式
在下文中，将参照附图通过具体的示例性实施方式和实施例对本发明的内容进行更详细地描述。应当注意，附图包括本发明的一些示例性实施方式，但不是所有的示例性实施方式。本说明书公开的发明内容可以以多种方式实施，并且不限于本文所描述的具体的示例性实施方式。本文公开的发明所属领域的普通技术人员将能够想到本文公开的发明内容的许多修改和其他示例性实施方式。因此，应当理解，本文公开的发明内容不限于本文描述的具体的示例性实施方式，其修改和其他示例性实施方式也在权利要求的范围内。
术语定义
下面给出本文所使用的主要术语的定义。
泛素蛋白连接酶E3成分n-识别蛋白(UBR)
本文所使用的术语UBR是指泛素蛋白连接酶E3成分n-识别蛋白的缩写。UBR是识别蛋白质的N-末端残基的N-识别蛋白，并且已知在哺乳动物中存在UBR1至UBR7至少7种类型。UBR是一种N-识别蛋白，并且与N-端规则途径相关，N-端规则途径是体内蛋白水解途径。具体而言，UBR识别蛋白质的N-末端降解信号(N-degron)，并且参与经由泛素蛋白酶体途径降解底物蛋白的过程。
UBR盒结构域
本文所使用的术语UBR盒结构域是存在于UBR蛋白中的结构域，并且是锌指基序。UBR蛋白包括UBR1至UBR7蛋白。UBR盒结构域被称为底物蛋白结合的结构域。本文公开的作为UBR盒结构域配体的化合物能够通过与UBR盒结构域结合来抑制UBR盒结构域底物结合。进一步地，本文公开的作为UBR盒结构域配体的化合物能够影响细胞内蛋白水解途径。
RING结构域
本文所使用的术语RING结构域已知存在于UBR1、UBR2和UBR3蛋白中。RING结构域也可以与RING泛素化结构域进行互换。RING结构域是存在于蛋白质中的结构域并且是锌指基序。RING结构域是在存在于E2中的泛素被转移至底物蛋白的过程中起重要作用的结构域，并且RING结构域用于允许泛素被转移至底物蛋白的过程在一个步骤中发生。
HECT结构域
本文所使用的术语HECT结构域已知存在于UBR5蛋白中。HECT结构域也可以与HECT泛素化结构域进行互换。HECT结构域是在存在于E2中的泛素被转移至底物蛋白的过程中起重要作用的结构域。存在于E2中的泛素被递送至HECT结构域，然后转移至底物蛋白。即，HECT结构域用于允许泛素被转移至底物蛋白的过程在两个步骤中发生。
锌指基序
如本文所使用的，术语锌指基序是指其中存在一个或多个锌离子以稳定蛋白质结构的蛋白质结构基序。本说明书的UBR盒结构域和RING结构域是锌指基序。
配体
如本文所使用的，术语配体是指与蛋白质特异性结合的材料。蛋白质包括酶或受体，当蛋白质为酶时，配体可以是指与酶结合的底物等，当蛋白质为受体时，配体可以是指与受体结合的激素等。
本文提供的作为UBR盒结构域配体的化合物是指与UBR盒结构域结合的化合物。作为实例，所述化合物是指与UBR蛋白中的UBR盒结构域结合的化合物。作为具体实例，所述化合物是指与存在于UBR1至UBR7的一种或多种蛋白质中的UBR盒结构域结合的化合物。然而，所述化合物不限于此。
本文提供的作为UBR盒结构域配体的化合物能够与UBR盒结构域的底物竞争性地起作用。即，所述化合物能够抑制UBR盒结构域的底物结合。另外，所述化合物能够通过抑制底物的结合来抑制底物的降解。
除非另有定义，否则本文所使用的所有技术术语和科学术语与本发明所属领域的普通技术人员通常理解的含义相同。本文提及的所有出版物、专利和其他参考文献均通过引用的方式将其整体并入。
在下文中，将公开本发明的具体内容。
Ⅰ.UBR盒结构域
1.概述
本文提供的作为UBR盒结构域配体的化合物与UBR盒结构域结合。UBR盒结构域被称为与N-末端残基序列或N-末端降解信号结合的结构域。该结构域与蛋白质通过N-端规则途径被降解的过程有关。因此，所述化合物可以经由N-端规则途径影响蛋白水解过程。
2.N-端规则途径
细胞通过蛋白水解调节蛋白质的量。在此情况下，已知蛋白质降解过程是通过识别作为蛋白质降解信号的degron的过程来进行的。具体而言，蛋白水解是根据蛋白质的N-末端残基序列进行调节，并且存在于N-末端的蛋白水解信号统称为N-degron。N-degron包括在N-末端具有带正电荷的残基(例如，精氨酸、赖氨酸和组氨酸)或大的疏水残基(苯丙氨酸、亮氨酸、色氨酸、异亮氨酸和酪氨酸)的那些N-degron。如上所述，基于蛋白质的半衰期由存在于蛋白质的N-末端的氨基酸残基所决定这一关联，使用了术语N-端规则。
3.UBR盒结构域
在N-端规则途径中，N-degron被N-识别蛋白识别，并且泛素蛋白连接酶E3成分n-识别蛋白(UBR)作为N-识别蛋白被发现。已知UBR通过UBR盒结构域识别N-末端残基序列或N-末端降解信号。即，UBR通过UBR盒结构域识别蛋白质降解信号，并且蛋白质的降解过程是通过蛋白质降解信号的识别来进行的。
通过UBR的蛋白质降解过程可以包括以下内容。UBR盒结构域识别具有N-末端降解信号的底物，泛素与底物结合，泛素结合的底物可以被蛋白酶体降解。即，具有N-末端降解信号的底物可以被泛素蛋白酶体***(UPS)降解。
Ⅱ.UBR盒结构域配体
1.概述
1)本说明书的化合物反映了UBR盒结构域的结构和与N-末端途径底物结合的特性。
本文公开的作为UBR盒结构域配体的化合物是考虑到UBR盒结构域的结构以及UBR盒结构域与N-末端途径底物的结合形式来进行设计的。
UBR盒结构域中存在的各种氨基酸通过离子相互作用、氢键、疏水相互作用等与N-末端途径底物中的氨基酸相互作用并结合。通过分析这些结合模式，本文合成并提供了能够与UBR盒结构域形成合适的结合模式的小分子化合物。进一步地，下文提供了根据式1的化合物。
2)本说明书的化合物具有增强与UBR盒结构域结合的结构。
1)式1
Figure BDA0004011798420000081
在上述式1中，A1为CH3或NH2。
在此情况下，本文公开的式1的化合物可以以立体异构体或其盐的形式存在，并且这种化合物的异构体或盐的形式包括在本说明书的范围内。
2)化合物的具体实例
i)化合物
作为实例，本文公开的作为UBR盒结构域配体的化合物可以选自以下描述的那些化合物：
[化合物1]
Figure BDA0004011798420000091
[化合物2]
Figure BDA0004011798420000092
在此情况下，作为化合物，可以考虑其可能的异构体的形式或其混合物的形式。例如，可以考虑包括所有的立体异构体，对映异构体和非对映异构体或其混合物(例如，外消旋混合物)。
ii)化合物的盐
作为本文公开的化合物，可以考虑其盐的形式。在此情况下，盐包括药学上可接受的盐。本文公开的盐包括酸加成盐或碱加成盐。形成盐的示例性酸包括盐酸、硫酸、磷酸、乙醇酸、乳酸、丙酮酸、柠檬酸、琥珀酸、戊二酸等，形成盐的示例性碱包括锂、钠、钾、钙、镁、甲胺、三甲胺等。然而，酸和碱不限于此，本领域技术人员可以容易地进行选择。
Ⅲ.化合物的用途
1.抑制UBR盒结构域底物结合
用于抑制UBR盒结构域底物结合的组合物
本文公开的化合物可以用来制备用于抑制UBR盒结构域底物结合的组合物。作为实例，包含本文公开的化合物的组合物可用于通过与UBR盒结构域结合来抑制UBR盒结构域底物结合。作为另一实例，包含所述化合物的组合物可用于防止与UBR盒结构域结合并被降解的底物被降解的用途。作为具体实例，包含所述化合物的组合物可用于防止与UBR盒结构域结合的底物被泛素-蛋白酶体途径降解的用途。
作为具体实例，包含本文公开的化合物的组合物可用于抑制底物的结合的用途，所述底物具有与UBR盒结构域结合的N-末端残基。作为具体实例，包含本文公开的化合物的组合物可用于抑制具有N-末端残基(例如精氨酸(Arg)、赖氨酸(Lys)、组氨酸(His)、色氨酸(Trp)、苯丙氨酸(Phe)、酪氨酸(Tyr)、亮氨酸(Leu)和异亮氨酸(Ile))的底物的结合的用途。然而，用途不限于此，该组合物可用于抑制本领域已知为UBR盒结构域底物的材料的结合的用途。
参照实施例，可以确认本文公开的化合物通过与UBR结合抑制了底物的降解(参见图1、图2和图3)。
2.UBR相关疾病的治疗
本说明书的化合物或其盐具有与UBR盒结构域结合的性质。即，本说明书的化合物是作为与UBR盒结构域结合的配体起作用的化合物。因此，这些化合物可用于抑制通过与体内的UBR盒结构域结合而被降解的蛋白质的降解，这种机制可用于治疗UBR相关疾病。
1)药物组合物
本文公开的化合物可以用来制备用于治疗有需要的受试者的药物组合物。
在此情况下，治疗包括具有改善特定医学病症的症状或延缓疾病进展的效果。在此情况下，受试者包括人类和非人类动物。在此情况下，药物组合物可以包含药学上可接受的载体、赋形剂和/或添加剂以及上述化合物。药学上可接受的载体、赋形剂和添加剂包括水、盐水、乙二醇、甘油、动植物脂肪、油、淀粉等，但不限于此，还包括药学上可接受的本领域已知的所有可接受的载体、赋形剂和/或添加剂。
2)治疗方法
本说明书提供了一种治疗方法，包括将本文公开的化合物或其药学上可接受的盐给予有需要的受试者。在此情况下，与未给予所述化合物或其盐的受试者相比，给予所述化合物或其药学上可接受的盐可具有减轻特定医学病症的症状或延缓疾病进展的效果。在此情况下，受试者包括人类和非人类动物。
-UBR相关疾病
作为实例，本说明书提供了一种治疗方法，包括将所述化合物或其药学上可接受的盐给予患有UBR相关疾病的受试者。即，本文公开的化合物或其药学上可接受的盐可用于治疗UBR相关疾病。作为具体实例，所述化合物或其药学上可接受的盐可用于通过抑制蛋白质的降解来治疗待治疗的特定疾病，其中，所述蛋白质通过与UBR盒结构域结合而被降解。
特定疾病包括：由肌肉营养不良(贝克型肌营养不良、先天性肌营养不良、杜兴氏肌营养不良、远端型肌营养不良、埃-德型肌营养不良、面肩肱型肌营养不良、肢带型肌营养不良、强直性肌营养不良、眼咽肌营养不良)引起的肌肉损失；由肌肉损失或退化介导的肌肉萎缩疾病，包括少肌症或癌症恶病质；由蛋白质过度降解引起的疾病，包括脂肪肉瘤、囊性纤维化、Johanson-Blizzard综合征、梗阻性尿路疾病(尿道阻塞序列征)、自身免疫性胰腺炎；或与UBR盒和UBR蛋白相关的已知疾病，包括Usher综合征。作为实例，所述化合物或其药学上可接受的盐可用于治疗由UBR介导的肌肉损失。例如，伴随疾病病症(例如癌症、败血症和甲状腺机能亢进)的肌肉质量的快速减少与肌内蛋白降解的增加有关，已知这与泛素蛋白酶体***的激活有关。在此情况下，已知泛素结合特别是通过激活N-端规则途径而增加，导致肌肉损失的发生[ALFRED L.GOLDBERG等人，1998，1999]。因此，通过与UBR盒结构域结合来防止肌肉损失途径的激活，本文公开的化合物或其药学上可接受的盐可用于治疗所述疾病。然而，本发明不限于此，特定疾病包括本领域已知的与UBR相关的疾病的所有疾病。
IV.实施例
实施例1.化合物的合成
[表1]
化合物列表
Figure BDA0004011798420000121
在Bruker Avance III 400MHz和Bruker Fourier 300MHz上记录1H NMR光谱，使用TMS作为内标。LCMS在以ES(+)或(-)电离模式运行的Agilent 1260HPLC和6120MSD(色谱柱：C18(50×4.6mm，5μm))的四极杆质谱仪上进行；T＝30℃；流速＝1.5mL/min；检测波长：220nm，254nm。
实验例1-1.化合物1(N-(5-乙酰基-2-氯苯基)-5-甲氧基戊酰胺)的制备
Figure BDA0004011798420000122
步骤1)B2的合成
在25℃下向处于MeOH(100mL)中的B1(四氢-2H-吡喃-2-酮，5.00g，50mmol，1.0eq)和原甲酸三甲酯(10.6g，100mmol，2.0eq)的混合物中滴加浓H2SO4(3mL)。将该混合物在65℃下搅拌16小时。在减压下将溶剂浓缩。添加8M氢氧化钠水溶液(10mL)，并将该混合物在80℃下搅拌2小时。冷却至10℃后，将反应混合物用4N HCl酸化，并用EA(50mL×3)萃取。将合并的有机层用盐水洗涤，经Na2SO4干燥，然后浓缩得到B2(5-甲氧基戊酸，4.0g，产率60％)，为无色油状物。
Figure BDA0004011798420000131
步骤2)化合物1的合成
将处于DMF(5mL)中的B2(5-甲氧基戊酸，0.2g，1.52mmol，1.0eq.)和HATU(0.69g，1.82mmol，1.2eq.)的混合物在25℃下搅拌30分钟。然后加入1-(3-氨基-4-氯苯基)乙-1-酮(0.26g，1.52mmol，1.0eq.)和三乙胺(0.31g，0.30mmol，2.0eq)。将该混合物在50℃下搅拌48小时。将该混合物倒入水(50mL)中，并用EA(50mL×3)萃取。将合并的有机层用盐水洗涤，经Na2SO4干燥，浓缩得到粗产物，将该粗产物通过制备型HPLC进行纯化。将收集的部分浓缩以除去大部分的CH3CN。将剩余部分冷冻干燥，得到化合物1(N-(5-乙酰基-2-氯苯基)-5-甲氧基戊酰胺，38mg，产率8.8％)，为白色固体。
Figure BDA0004011798420000132
实验例1-2.化合物2(4-氯-3-(5-甲氧基戊酰胺基)苯甲酰胺)的制备
Figure BDA0004011798420000133
将处于DMF(5mL)中的B2(5-甲氧基戊酸，0.2g，1.52mmol，1.0eq)和HATU(0.69g，1.82mmol，1.2eq)的混合物在25℃下搅拌30分钟。然后加入3-氨基-4-氯苯甲酰胺(0.26g，1.52mmol，1.0eq)和三乙胺(0.31g，0.30mmol，2.0eq)。将该混合物在50℃下搅拌48小时。将该混合物倒入水(50mL)中，并用EA(50mL×3)萃取。将合并的有机层用盐水洗涤，经Na2SO4干燥，浓缩得到粗产物，将该粗产物通过制备型HPLC进行纯化。将收集的部分浓缩以除去大部分的CH3CN。将剩余部分冷冻干燥，得到化合物2(4-氯-3-(5-甲氧基戊酰胺基)苯甲酰胺，48mg，产率11.1％)，为黄色固体。
Figure BDA0004011798420000141
实施例2.结合测定实验
实施例2-1使用免疫印迹法确认肌动蛋白是否为Arg/N-degron途径底物。
使用含有10％ FBS和1％链霉素/青霉素的DMEM培养基在保持5％二氧化碳的培养箱中培养L6细胞系，培养后将细胞等分到12孔板中，其中，L6细胞系是大鼠肌源细胞。将细胞额外培养24小时以使其完全附着至板的表面。为了确认MG132是否增加了UBR1结合，在用MG132(10μM)单独处理24小时后收集细胞。为了从收集的细胞中提取蛋白质，将50μL裂解缓冲液(20mM Tris，pH 7.4，150mM NaCl，1％Triton-X-100，2mM NaF，2mM EDTA，2mM b-甘油磷酸盐(b-glycerophosphate)，5mM原钒酸钠，1mM PMSF，亮肽素，抑肽酶(aprotinin))注射到每个样品中，将细胞裂解。根据测得的总蛋白质浓度，向每个样品中加入样品缓冲液，并使混合物在100℃反应5分钟。从完全反应的样品中取出5μL并等分到丙烯酰胺凝胶的每个孔中后，进行免疫印迹法，[图1]中对实验结果进行了说明。
对于免疫印迹法，代表性的实验由三个以上的独立实验概括而成。
参照图1，确认了与对照相比，ACTA1、ACTC1和ACTG2的水平通过MG132得以增加。进一步地，确认了当UBR蛋白被敲低(knock down)时ACTA1和ACTG2的水平增加。即，可以确认肌动蛋白是Arg/N-degron途径底物。
实施例2-2通过体外转录/翻译方法确认R-nsP4降解的抑制
使用
Figure BDA0004011798420000142
快速耦合转录/翻译***试剂盒来确认化合物的R-nsP4表达。在使用Transcend生物素-赖氨酰-tRNA、蛋氨酸、苯丁抑制素(bestatin)、TnT quick Master mix和DHFR-Ub-R-nsP4质粒制备预混物后，将该预混物与化合物(1μM)混合。每个样品在30℃反应40分钟后，向其中加入5X SDS上样染料。使所得混合物在95℃反应2分钟后，取出5μL等分到丙烯酰胺凝胶的每个孔中，然后进行免疫印迹法，[图2]中对实验结果进行了说明。对于体外转录/翻译方法，代表性的实验由三个以上的独立实验概括而成。
参照图2，可以确认与对照相比，R-nsP4的水平通过化合物1、化合物2得以增加。即，可以确认在用本发明的化合物进行处理的情况下，R-nsP4水平通过与UBR1结合而增加。
实施例2-3通过免疫印迹对肌细胞肌动蛋白降解的抑制的评估
为了评估肌细胞中的化合物的肌动蛋白降解，使用含有10％ FBS和1％链霉素/青霉素的DMEM培养基在保持5％二氧化碳的培养箱中培养L6细胞系，L6细胞系是大鼠肌源细胞。为了根据选自本发明化合物的代表性化合物的处理来测量UBR1结合强度，将细胞等分到12孔板中。将细胞额外培养24小时使其完全附着至板的表面。在用化合物(5μM)单独处理24小时后收集细胞，以确认化合物是否增加了UBR1结合。为了从收集的细胞中提取蛋白质，将50μL裂解缓冲液(20mM Tris，pH 7.4，150mM NaCl，1％ Triton-X-100，2mM NaF，2mMEDTA，2mM b-甘油磷酸盐，5mM原钒酸钠，1mM PMSF，亮肽素，抑肽酶)注射到每个样品中，将细胞裂解。根据测得的总蛋白质浓度，向每个样品中加入样品缓冲液，使混合物在100℃反应5分钟。从完全反应的样品中取出5μL并等分到丙烯酰胺凝胶的每个孔中后，进行免疫印迹法，[图3]中对实验结果进行了说明。对于免疫印迹法，代表性的实验由三个以上的独立实验概括而成。
参照图3，可以确认ACTA1的水平通过化合物1、化合物2得以进一步增加。即，可以确认在用本发明的化合物进行处理的情况下，肌内蛋白质ACTA1的降解通过与UBR1结合而受到抑制。
实施例2-4使用MST测定UBR1与化合物之间有无结合
1)UBR1蛋白的制备
对应于人UBR1(UniProt ID:Q8IWV7)的UBR盒的Gln97-Pro168部分被克隆到经修饰的表达载体中，然后在大肠杆菌中进行表达。在使用亲和色谱法之后，通过蛋白酶去除标签，然后将Gly-His-Met添加到N-末端。在进行离子色谱法之后，使用凝胶过滤色谱法在10mM NaCl、20mM Tris-HCl、2mM beta-巯基乙醇的缓冲组合物(pH 7.5)中对UBR1的最终UBR盒蛋白进行纯化。
2)UBR1 UBR盒蛋白标记
Monolith蛋白质标记试剂盒RED-NHS第二代(Cat#MO-L011)的染料具有与伯胺(赖氨酸残基)形成共价键的NHS-酯基团。针对配备有RED检测器的Monolith系列设备，对该染料进行了优化。根据提出的方案，使用该试剂盒对纯化的UBR1 UBR盒蛋白进行标记。
3)使用MST测量UBR1和配体之间有无结合
热泳是指粒子由于温度梯度而移动的现象。存在于高温区域的粒子比存在于低温区域的粒子具有更大的动能，并且以更大的能量与周围的粒子更频繁地碰撞。结果，粒子从高温区域向低温区域移动。
蛋白质的热泳通常不同于蛋白质-配体复合物的热泳。这是因为配体的结合改变了它的大小、电荷和溶剂化能。进一步地，即使配体结合不显著改变蛋白质的大小和电荷，MST也可以检测由配体结合引起的蛋白质分子的溶剂熵的变化。因此，使用MST测量了UBR1UBR盒蛋白和配体化合物的结合，确认了所提出的配体与UBR1 UBR盒结合。

Claims (4)

1.一种具有式1结构的化合物或其盐：
[式1]
Figure FDA0004011798410000011
其中，A1为CH3或NH2。
2.一种用于抑制UBR盒结构域底物结合的组合物，其中，所述组合物包含权利要求1所述的化合物或其盐。
3.一种用于治疗UBR相关疾病的药物组合物，其中，所述组合物包含权利要求1所述的化合物或其药学上可接受的盐。
4.如权利要求3所述的药物组合物，其中，所述UBR相关疾病包括：由肌肉营养不良(贝克型肌营养不良、先天性肌营养不良、杜兴氏肌营养不良、远端型肌营养不良、埃-德型肌营养不良、面肩肱型肌营养不良、肢带型肌营养不良、强直性肌营养不良、眼咽肌营养不良)引起的肌肉损失；由肌肉损失或退化介导的肌肉萎缩疾病，包括少肌症或癌症恶病质；由蛋白质过度降解引起的疾病，包括脂肪肉瘤、囊性纤维化、Johanson-Blizzard综合征、梗阻性尿路疾病(尿道阻塞序列征)、自身免疫性胰腺炎；或与UBR盒和UBR蛋白相关的已知疾病，包括Usher综合征。
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