TW202206407A - 用於ｕｂｒ盒結構域配體之化合物、組成物以及醫藥組成物 - Google Patents

用於ｕｂｒ盒結構域配體之化合物、組成物以及醫藥組成物 Download PDF

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TW202206407A
TW202206407A TW110115113A TW110115113A TW202206407A TW 202206407 A TW202206407 A TW 202206407A TW 110115113 A TW110115113 A TW 110115113A TW 110115113 A TW110115113 A TW 110115113A TW 202206407 A TW202206407 A TW 202206407A
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TW110115113A
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權容兌
金昡兌
羅貞恩
徐裕珍
池昌勛
崔荷琳
李知垠
許雅貞
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南韓商奧士擇破利悟股份有限公司
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Abstract

本說明書是關於一種作為UBR盒結構域配體的化合物。本說明書提供一種與UBR盒結構域結合的小分子化合物。此外，本說明書提供一種用於抑制UBR盒結構域基質結合的組成物，包含與UBR盒結構域結合的配體化合物、用於治療UBR相關疾病的醫藥組成物以及其用途。

Description

作為UBR盒結構域配體之化合物
本說明書中所揭露的內容是關於作為UBR盒結構域配體的化合物。UBR盒結構域為通常存在於N端規則路徑的泛素蛋白連接酶E3組分n-識別蛋白（UBR）蛋白中的結構域。在此情況下，UBR盒結構域稱為基質所結合的結構域。UBR盒結構域對於與基質的N末端殘基結合以在基質中形成多泛素鏈是必需的，且已知基質藉由此過程降解。
本說明書是關於用作與UBR盒結構域結合的配體的化合物。
細胞藉由降解蛋白質調節活體內蛋白質的量及功能。在此情況下，活體內蛋白質可取決於N末端殘基序列而降解，且此類降解路徑稱為N端規則路徑。亦即，N端規則路徑為使用特定蛋白質N端作為降解信號的蛋白水解系統。N端規則路徑可包含以下蛋白水解過程。
在真核生物的情況下，N-識別蛋白識別蛋白質的N末端降解信號，且N-識別蛋白可藉由允許泛素與待降解的蛋白質結合來降解蛋白質。在此情況下，N末端降解信號可包含在N末端具有帶正電荷的殘基（類型1：例如精胺酸、離胺酸以及組胺酸）或較大疏水性殘基（類型2：苯丙胺酸、白胺酸、色胺酸、異白胺酸及酪胺酸）的彼等N末端降解信號。本發明人首次發現或選殖N-識別蛋白UBR 1、UBR2、UBR3以及UBR5，且揭露N-識別蛋白具有作為基質識別結構域的UBR盒結構域（Tasaki等人 2005）。在此情況下，將由N-識別蛋白與N端規則配體的結合所產生的泛素化基質遞送至蛋白酶體且降解為短肽。在此過程中，特定N末端殘基（Nt-Arg、Nt-His、Nt-Lys、Nt-Trp、Nt-Phe、Nt-Tyr、Nt-Leu、Nt-Leu）提供在N-識別蛋白靶向N端規則受質時所需的大部分氫鍵，且因此為結合所必需的決定子（determinant）（Sriram及Kwon, 2010）。
UBR為泛素蛋白連接酶E3組分n-識別蛋白的縮寫，且UBR為識別蛋白質的N末端降解信號的N-識別蛋白。已知至少7種類型的UBR 1至UBR 7存在於哺乳動物中。此外，UBR共同具有的UBR盒結構域是大小為約70個殘基的鋅指模體，且稱為高度保守的基質結合結構域。[Kwon等人, 1998; Xie及Varshavsky, 1999; Kwak等人, 2004; Varshavsky, 1996; Varshavsky,1997; Kwon等人, 2011; 以及Zenker等人, 2014].
亦即，UBR為與N端規則路徑相關的N-識別蛋白，所述N端規則路徑為蛋白水解路徑，且UBR中的UBR盒結構域為基質結合結構域。特定而言，在UBR 1至UBR 7中，已知UBR1、UBR2、UBR3以及UBR5充當泛素蛋白接合酶E3且具有RING結構域或HECT結構域。與UBR結合的N端規則基質藉由泛素蛋白酶體路徑降解。特定而言，UBR中的UBR盒結構域識別基質的N末端胺基酸且經由RING結構域或HECT結構域將基質泛素化，由此經由蛋白酶體路徑降解基質。舉例而言，當錯誤摺疊蛋白質保留在細胞中持續延長時段時，蛋白質可能聚集以阻斷蛋白酶體或降低其他細胞功能，且因此經由泛素蛋白酶體路徑降解（Ji及Kwon, 2017）。
亦即，UBR盒結構域藉由識別N末端降解信號而在胞內蛋白水解路徑中起重要作用。因此，與UBR盒結構域結合的配體可能影響胞內蛋白水解路徑。
如上文所描述，本說明書是關於一種作為配體的化合物，所述配體與同胞內蛋白水解路徑相關的UBR盒結構域結合。
技術問題
本說明書提供一種與UBR盒結構域結合的小分子化合物。在此情況下，UBR盒結構域包含UBR 1至UBR7中的UBR盒結構域。小分子化合物可充當適合於與UBR盒結構域結合的配體。
在一個實施例中，本說明書提供一種用於抑制UBR盒結構域基質結合的組成物，包括與UBR盒結構域結合的配體化合物。
在一個特定實施例中，本說明書提供一種用於治療UBR相關疾病的醫藥組成物及其用途，且所述組成物包括與UBR盒結構域結合的配體化合物。
在一更特定實施例中，本說明書提供一種用於治療疾病的醫藥組成物，所述疾病包含由肌肉萎縮症（貝克爾（Becker）、先天性、杜興氏（Duchenne）、遠端型、埃-德二氏（Emery-Dreifuss）、面肩臂、肢帶型、肌強直性、眼咽部（ocuophargyngeal））引起的肌肉損失；由肌肉損失或降解介導的肌肉萎縮疾病，包含肌肉減少症或癌症惡病質；由過度的蛋白質降解引起的疾病，包含脂肪肉瘤、囊腫纖維化、約翰遜-布利澤德症候群（Johanson-Blizzard syndrome）、阻塞性尿路疾病（尿道阻塞序列）；自體免疫性胰臟炎；或與UBR盒及UBR蛋白相關的已知疾病，包含尤塞氏症候群（Usher syndrome），及其用途，且所述組成物包括與UBR盒結構域結合的配體化合物。 技術解決方案
本說明書提供一種具有式1結構的化合物或其鹽。 [式1]
Figure 02_image001
其中A1 為CH3 或NH2 。
在此情況下，作為一實例，本說明書提供一種用於抑制UBR盒結構域基質結合的組成物，包括化合物或其鹽，其中A1 為CH3 或NH2 。
在此情況下，作為一實例，本說明書提供一種用於治療UBR相關疾病的醫藥組成物，包括化合物或其醫藥學上可接受的鹽，其中A1 為CH3 或NH2 ；及一種藉由使用化合物來治療UBR相關疾病的方法。
在此情況下，作為一實例，UBR相關疾病可選自由肌肉萎縮症（貝克爾、先天性、杜興氏、遠端型、埃-德二氏、面肩臂、肢帶型、肌強直性、眼咽部）引起的肌肉損失；由肌肉損失或降解介導的肌肉萎縮疾病，包含肌肉減少症或癌症惡病質；由過度的蛋白質降解引起的疾病，包含脂肪肉瘤、囊腫纖維化、約翰遜-布利澤德症候群、阻塞性尿路疾病（尿道阻塞序列）；自體免疫性胰臟炎；或尤塞氏症候群。 有利效應
本文所揭露的發明提供一種相對於UBR盒結構域具有高結合強度的配體化合物。
經由UBR盒結構域配體化合物可抑制UBR盒結構域基質結合，且可提供利用此特徵的各種應用。舉例而言，UBR相關疾病（例如，肌肉減少症及類似者）可藉由UBR盒結構域配體化合物來治療。
在下文中，將參考隨附圖式經由特定例示性實施例及實例更詳細地描述本發明內容。應注意，隨附圖式包含本發明的一些例示性實施例，但並非所有例示性實施例。由本說明書揭露的本發明內容可不同地實施，且不限於本文中所描述的特定例示性實施例。本文中揭露的發明所涉及的所屬領域中具有通常知識者將能夠設想本文所揭露的發明內容的許多修改及其他例示性實施例。因此，應理解，本文所揭露的本發明內容不限於本文所描述的特定例示性實施例，且其修改及其他例示性實施例亦在申請專利範圍的範疇內。術語的定義
下文給出本文中所使用的主要術語的定義。泛素蛋白 連接酶 E3 組分 n- 識別蛋白（ UBR ）
如本文所使用的術語UBR指代泛素蛋白連接酶E3組分n-識別蛋白的縮寫。UBR為識別蛋白質的N末端殘基的N-識別蛋白，且已知至少7種類型的UBR 1至UBR 7存在於哺乳動物中。UBR為N-識別蛋白且與N端規則路徑相關，所述N端規則路徑為活體內蛋白水解路徑。特定而言，UBR識別蛋白質的N末端降解信號（N-降解決定子），且參與經由泛素蛋白酶體路徑降解基質蛋白的過程。UBR 盒結構域
本文所使用的術語UBR盒結構域為存在於UBR蛋白中的結構域，且為鋅指模體。UBR蛋白包含UBR 1至UBR 7蛋白。UBR盒結構域稱為基質蛋白所結合的結構域。本文所揭露的作為UBR盒結構域配體的化合物可藉由與UBR盒結構域結合來抑制UBR盒結構域基質結合。此外，本文所揭露的作為UBR盒結構域配體的化合物可影響胞內蛋白水解路徑。RING 結構域
已知本文所使用的術語RING結構域存在於UBR 1、UBR2以及UBR3蛋白中。RING結構域亦可與RING泛素化結構域互換。RING結構域為存在於蛋白質中的結構域且為鋅指模體。RING結構域為在將存在於E2中的泛素轉移至基質蛋白的過程中起重要作用的結構域，且RING結構域用於允許在一個步驟中進行將泛素轉移至基質蛋白的過程。HECT 結構域
已知本文所使用的術語HECT結構域存在於UBR 5蛋白中。HECT結構域亦可與HECT泛素化結構域互換。HECT結構域為在將存在於E2中的泛素轉移至基質蛋白的過程中起重要作用的結構域。將存在於E2中的泛素遞送至HECT結構域且隨後轉移至基質蛋白。亦即，HECT結構域用於允許在兩個步驟中進行將泛素轉移至基質蛋白的過程。鋅 指模體
如本文所使用，術語鋅指模體指代其中存在一或多個鋅離子以使蛋白質結構穩定的蛋白質結構模體。本說明書的UBR盒結構域及RING結構域為鋅指模體。配體
如本文所使用，術語配體指代與蛋白質特異性結合的物質。蛋白質包含酶或受體，且當蛋白質為酶時，配體可指代與酶結合的基質或類似物，且當蛋白質為受體時，配體可指代與受體結合的激素或類似物。
本文所提供的作為UBR盒結構域配體的化合物意謂與UBR盒結構域結合的化合物。作為一實例，化合物指代與UBR蛋白中的UBR盒結構域結合的化合物。作為一特定實例，化合物指代與存在於UBR 1至UBR 7的一或多種蛋白質中的UBR盒結構域結合的化合物。然而，化合物不限於此。
本文所提供的作為UBR盒結構域配體的化合物可與UBR盒結構域的基質競爭性地起作用。亦即，化合物可抑制UBR盒結構域的基質結合。另外，化合物可藉由抑制基質的結合來抑制基質的降解。
除非另外定義，否則本文所用的所有技術及科學術語均具有與本發明所涉及的所屬領域中具有通常知識者通常所理解相同的含義。本文提及的所有公開案、專利以及其他參考案均以全文引用的方式併入本文中。
在下文中，將揭露本發明的具體內容。I. UBR 盒結構域 1. 概述
本文所提供的作為UBR盒結構域配體的化合物與UBR盒結構域結合。UBR盒結構域稱為N末端殘基序列或N末端降解信號所結合的結構域。結構域與蛋白質藉由N端規則路徑降解的過程相關。因此，化合物可經由N端規則途徑影響蛋白水解過程。2. N 端規則路徑
細胞經由蛋白水解調節蛋白質的量。在此情況下，已知藉由識別降解決定子（其為蛋白質的降解信號）的過程來執行蛋白質降解過程。特定而言，蛋白水解取決於蛋白質的N-末端殘基序列而調節，且存在於N末端處的蛋白水解信號統稱為N-降解決定子。N-降解決定子包含在N末端處具有帶正電荷的殘基（例如，精胺酸、離胺酸以及組胺酸）或較大疏水性殘基（苯丙胺酸、白胺酸、色胺酸、異白胺酸以及酪胺酸）的彼等N-降解決定子。如上文所描述，已基於蛋白質的半衰期藉由存在於蛋白質的N末端處的胺基酸殘基判定的關聯來使用術語N端規則。3. UBR 盒結構域
在N端規則路徑中，N-降解決定子由N-識別蛋白識別且泛素蛋白連接酶E3組分n-識別蛋白（UBR）被發現為N-識別蛋白。已知UBR藉由UBR盒結構域識別N末端殘基序列或N末端降解信號。亦即，UBR經由UBR盒結構域識別蛋白質降解信號，且經由識別蛋白質降解信號來執行蛋白質降解過程。
由UBR進行的蛋白質降解過程可包含以下內容。UBR盒結構域識別具有N末端降解信號的基質，泛素與基質結合，且泛素結合的基質可由蛋白酶體降解。亦即，具有N末端降解信號的基質可由泛素蛋白酶體系統（ubiquitin proteasome system；UPS）降解。II. UBR 盒結構域配體 1. 概述 1 ） 本說明書的化合物反映 UBR 盒結構域的結構及與 N 末端路徑基質結合的特徵
考慮到UBR盒結構域的結構及UBR盒結構域及N末端路徑基質的結合形式，設計本文所揭露的作為UBR盒結構域配體的化合物。
存在於UBR盒結構域中的各種胺基酸經由離子相互作用、氫鍵結、疏水相互作用及類似者與N末端路徑基質中的胺基酸相互作用且與N端路徑基質中的胺基酸結合。藉由分析此等結合模式，在本文中合成且提供能夠與UBR盒結構域形成適合結合模式的小分子化合物。此外，下文提供根據式1的化合物。2 ） 本說明書的化合物具有增強與 UBR 盒結構域結合的結構。 1）式1
Figure 02_image002
[式1]
在上文式1中，A1 為CH3 或NH2 。
在此情況下，本文所揭露的式1化合物可以立體異構體或其鹽的形式存在，且此類化合物的異構體或鹽的形式包含於本說明書的範疇中。 2）化合物的特定實例 i）化合物
作為一實例，本文所揭露的作為UBR盒結構域配體的化合物可選自以下所描述的彼等化合物： [化合物1]
Figure 02_image003
[化合物2]
Figure 02_image004
在此情況下，可考慮其可能的異構體形式或其混合物形式作為化合物。舉例而言，可考慮所有立體異構體，包含對映異構體及非對映異構體，或其混合物（例如，外消旋混合物）。 ii）化合物的鹽，
作為本文所揭露的化合物，可考慮其鹽形式。在此情況下，所述鹽含有醫藥學上可接受的鹽。本文所揭露的鹽包含酸加成鹽或鹼加成鹽。形成鹽的例示性酸包含鹽酸、硫酸、磷酸、乙醇酸、乳酸、丙酮酸、檸檬酸、丁二酸、戊二酸及類似者，且形成鹽的例示性鹼包含鋰、鈉、鉀、鈣、鎂、甲胺、三甲胺及類似者。然而，酸及鹼不限於此且可容易地由所屬領域中具通常知識者選擇。III. 化合物的用途 1.UBR 盒結構域基質結合的抑制 用於抑制 UBR 盒結構域基質結合的組成物
本文所揭露的化合物可用於製備用於抑制UBR盒結構域基質結合的組成物。作為一實例，包含本文所揭露的化合物的組成物可用於藉由與UBR盒結構域結合來抑制UBR盒結構域基質結合。作為另一實例，包含化合物的組成物可用於防止與UBR盒結構域結合且降解的基質降解的用途。作為一特定實例，包含化合物的組成物可用於防止與UBR盒結構域結合的基質由泛素蛋白酶體路徑降解的用途。
作為一特定實例，包含本文所揭露的化合物的組成物可用於抑制具有與UBR盒結構域結合的N末端殘基的基質的結合的用途。作為一特定實例，包含本文所揭露的化合物的組成物可用於抑制具有N末端殘基的基質的結合的用途，所述N末端殘基諸如精胺酸（Arg）、離胺酸（Lys）、組胺酸（His）、色胺酸（Trp）、苯丙胺酸（Phe）、酪胺酸（Tyr）、白胺酸（Leu）以及異白胺酸（Ile）。然而，所述用途不限於此，所述組成物可用於抑制所屬領域中已知為UBR盒結構域的基質的物質的結合的用途。
參看實例，可確認本文所揭露的化合物藉由與UBR結合來抑制基質的降解（參見圖1、圖2以及圖3）。2. UBR 相關疾病的治療
本說明書的化合物或其鹽具有與UBR盒結構域結合的特性。亦即，本說明書的化合物為充當與UBR盒結構域結合的配體的化合物。因此，此等化合物可用於抑制藉由與體內的UBR盒結構域結合而降解的蛋白質的降解，且此類機制可用於治療UBR相關疾病。1 ）醫藥組成物
本文所揭露的化合物可用於製備用於治療有需要的個體的醫藥組成物。
在此情況下，治療包含具有改善特定醫學病況的症狀或延緩疾病發展的作用。在此情況下，個體包含人類及非人類動物。在此情況下，醫藥組成物可包含為醫藥學上可接受的載體、賦形劑及/或添加劑，以及前述化合物。醫藥學上可接受的載體、賦形劑以及添加劑包含水、鹽水、乙二醇、丙三醇、動物及植物脂肪、油、澱粉及類似物，但不限於此，且包含醫藥學上可接受的所屬領域中已知的所有可接受的載體、賦形劑及/或添加劑。2 ）治療方法
本說明書提供一種治療方法，包含向有需要的個體投與本文所揭露的化合物或其醫藥學上可接受的鹽。在此情況下，與未投與化合物或其鹽的個體相比，投與化合物或其醫藥學上可接受的鹽可具有緩解特定醫學病況的症狀或延緩疾病發展的作用。在此情況下，個體包含人類及非人類動物。-UBR 相關疾病
作為一實例，本說明書提供一種治療方法，包含向患有UBR相關疾病的個體投與化合物或其醫藥學上可接受的鹽。亦即，本文所揭露的化合物或其醫藥學上可接受的鹽可用於治療UBR相關疾病。作為一特定實例，化合物或其醫藥學上可接受的鹽可用於藉由抑制藉由與UBR盒結構域結合而降解的蛋白質的降解來治療待治療的特定疾病。
特定疾病包含肌肉萎縮症（貝克爾、先天性、杜興氏、遠端型、埃-德二氏、面肩臂、肢帶型、肌強直性、眼咽部）引起的肌肉損失；由肌肉損失或降解介導的肌肉萎縮疾病，包含肌肉減少症或癌症惡病質；由過度的蛋白質降解引起的疾病，包含脂肪肉瘤、囊腫纖維化、約翰遜-布利澤德症候群、阻塞性尿路疾病（尿道阻塞序列）；自體免疫性胰臟炎；或與UBR盒及UBR蛋白相關的已知疾病，包含尤塞氏症候群。作為一實例，化合物或其醫藥學上可接受的鹽可用於治療由UBR介導的肌肉損失。舉例而言，伴隨著諸如癌症、敗血症以及甲狀腺高能症之疾病病況的肌肉質量的快速損失與肌肉內蛋白質的降解的增加相關，已知所述降解與泛素蛋白酶體系統的活化相關。在此情況下，已知泛素結合尤其藉由活化N端規則途徑而增加，從而引起肌肉損失的出現[ALFRED L GOLDBERG等人 1998, 1999]。因此，本文所揭露的化合物或其醫藥學上可接受的鹽可用於藉由與UBR盒結構域結合而防止肌肉損失路徑的活化來治療疾病。然而，本發明不限於此，且特定疾病包含所屬領域中已知為與UBR相關的疾病的所有疾病。V. 實例 實例 1. 化合物的合成 [表1] 化合物的列表
化合物編號 化合物的名稱
1
Figure 02_image005
N-(5-乙醯基-2-氯苯基)-5-甲氧基戊醯胺
2
Figure 02_image006
4-氯-3-(5-甲氧基戊醯胺)苯甲醯胺
1 H NMR光譜記錄在Bruker Avance III 400 MHz及Bruker Fourier 300 MHz上且使用TMS作為內標。LCMS在Agilent 1260HPLC及6120MSD（管柱：C18（50×4.6毫米，5微米）上的四極質譜儀上進行，以ES（+）或（-）電離模式操作；T = 30℃；流動速率= 1.5毫升/分鐘；所偵測波長：220奈米、254奈米。 實驗實例 1-1. 製備化合物 1 （ N-(5- 乙醯基 -2- 氯苯基 )-5- 甲氧基戊醯胺 ）
Figure 02_image007
步驟1）合成B2
在25℃下向B1（四氫-2H-哌喃-2-酮，5.00公克，50毫莫耳，1.0當量）及原甲酸三甲酯（10.6公克，100毫莫耳，2.0當量）於MeOH（100毫升）中的混合物中逐滴添加濃H2SO4（3毫升）。將混合物在65℃下攪拌16小時。在減壓下濃縮溶劑。添加8 M氫氧化鈉水溶液（10毫升）且將混合物在80℃下攪拌2小時。冷卻至10℃後，反應混合物用4 N HCl酸化且用EA（50毫升×3）萃取。將合併的有機層用鹽水洗滌，經Na2SO4乾燥且濃縮，得到呈無色油狀物的B2（5-甲氧基戊酸，4.0公克，產率60%）。 1HNMR (CDCl3, 400 MHz): δ 3.41 (t, J = 6.0 Hz, 2H), 3.34 (s, 3H), 2.39 (t, J = 7.6 Hz, 2H), 1.62-1.74 (m, 4H)。 步驟2）合成化合物1
將B2（5-甲氧基五甲酸，0.2公克，1.52毫莫耳，1.0當量）及HATU（0.69公克，1.82毫莫耳，1.2當量）於DMF（5毫升）中的混合物在25℃下攪拌30分鐘。隨後添加1-(3-胺基-4-氯苯基)乙-1-酮（0.26公克，1.52毫莫耳，1.0當量）及三乙胺（0.31公克，0.30毫莫耳，2.0當量）。將混合物在50℃下攪拌48小時。將混合物倒入水（50毫升）中且用EA（50毫升×3）萃取。將合併的有機層用鹽水洗滌，經Na2SO4乾燥且濃縮，以得到粗產物，藉由製備型HPLC純化所述粗產物。將收集的溶離份濃縮以移除大部分CH3CN。殘餘溶離份經冷凍乾燥，以得到呈白色固體狀的化合物1（N-(5-乙醯基-2-氯苯基）-5-甲氧基戊醯胺，38毫克，產率8.8%）。 1HNMR (CDCl3, 400 MHz): δ 9.03 (s, 1H), 7.84 (s, 1H), 7.67 (dd, J = 8.4 Hz, 2 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 3.45 (t, J = 6.4 Hz, 2H), 3.35 (s, 3H), 2.61 (s, 3H), 2.52 (t, J = 7.2 Hz, 2H), 1.85-1.88 (m, 2H), 1.69-1.73 (m, 2H)。 LCMS；質量計算值：283.7；MS實驗值：283.9。實驗實例 1-2. 製備化合物 2 （ 4- 氯 -3-(5- 甲氧基戊醯胺 ) 苯甲胺 ）
Figure 02_image009
將B2（5-甲氧基五甲酸，0.2公克，1.52毫莫耳，1.0當量）及HATU（0.69公克，1.82毫莫耳，1.2當量）於DMF（5毫升）中的混合物在25℃下攪拌30分鐘。隨後添加3-胺基-4-氯苯甲醯胺（0.26公克，1.52毫莫耳，1.0當量）及三乙胺（0.31公克，0.30毫莫耳，2.0當量）。將混合物在50℃下攪拌48小時。將混合物倒入水（50毫升）中且用EA（50毫升×3）萃取。將合併的有機層用鹽水洗滌，經Na2SO4乾燥且濃縮，以得到粗產物，藉由製備型HPLC純化所述粗產物。將收集的溶離份濃縮以移除大部分CH3CN。將殘餘溶離份冷凍乾燥，以得到呈黃色固體狀的化合物2（4-氯-3-(5-甲氧基戊醯胺)苯甲醯胺，48毫克，產率11.1%）。 1HNMR (CDCl3, 400 MHz): δ 8.82 (s, 1H), 7.89 (s, 1H), 7.64 (dd, J = 8.4 Hz, 2 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 5.93-6.38 (m, 2H), 3.45 (t, J = 6.0 Hz, 2H), 3.36 (s, 3H), 3.52 (t, J = 7.2 Hz, 2H), 1.81-1.88 (m, 2H), 1.66-1.73 (m, 2H)。 LCMS；質量計算值：284.7；MS實驗值：284.9。實例 2. 結合分析實驗 實例 2-1 使用免疫墨點法確認肌肉肌動蛋白是否為 Arg /N- 降解決定子 路徑基質 。
在其中維持5%二氧化碳的培育箱中使用含有10% FBS及1%鏈黴素/青黴素的DMEM介質培養L6細胞株（其為大鼠肌原性細胞），且將細胞在培養之後等分至12孔盤中。將細胞另外培養24小時以便完全附著至盤的表面。為確認MG132是否增加UBR1結合，在單獨用MG132（10微莫耳）處理24小時之後收集細胞。為自所收集的細胞提取蛋白質，將50微升的裂解緩衝液（20 mM Tris（pH 7.4）、150 mM NaCl、1% Triton-X-100、2 mM NaF、2 mM EDTA、2 mM b-甘油磷酸鹽、5 mM原釩酸鈉、1 mM PMSF、抗纖維蛋白溶酶肽、抑肽酶）注射至各樣品中，且裂解細胞。基於所量測的總蛋白質濃度，將樣品緩衝液添加至各樣品中且使混合物在100℃下反應5分鐘。在自完全反應的樣品取出5微升且等分至丙烯醯胺凝膠的各孔中之後，執行免疫墨點法，且實驗結果示出在[圖1]中。
對於免疫墨點法，根據三個或超過三個獨立實驗示意性展示一代表性實驗。
參看圖1，已確認相較於對照，ACTA1、ACTC1以及ACTG2的含量藉由MG132增加。此外，已確認當UBR蛋白被阻斷基因表現時，ACTA1及ACTG2的含量增加。亦即，可確認肌肉肌動蛋白為Arg/N-降解決定子路徑基質。實例 2-2 藉由活體外轉錄 / 轉譯法確認 R-nsP4 降解的 抑制
TnT®快速偶合轉錄/轉譯系統套組用於確認化合物的R-nsP4表現。在使用Transcend Biotin-Lysyl-tRNA、甲硫胺酸、貝他定（bestatin）、TnTquick主混合物及DHFR-Ub-R-nsP4質體製備預混物之後，將預混物與化合物（1微莫耳）混合。在使各樣品在30℃下反應40分鐘之後，向其中添加5X SDS負載染料。在使所得混合物在95℃下反應2分鐘之後，獲取5微升且等分至丙烯醯胺凝膠的各孔中，且隨後執行免疫墨點法，且實驗結果示出在[圖2]中。對於活體外轉錄/轉譯法，根據三個或超過三個獨立實驗示意性展示一代表性實驗。
參看圖2，可確認相較於對照，R-nsP4的含量藉由化合物1、化合物2增加。亦即，可確認在用根據本發明的化合物處理的情況下，R-nsP4含量藉由與UBR1結合而增加。實例 2-3 藉由免疫墨點評估肌肉細胞肌動蛋白降解的抑制
為評估化合物在肌肉細胞中的肌動蛋白降解，在其中維持5%二氧化碳的培育箱中使用含有10% FBS及1%鏈黴素/青黴素的DMEM介質培養L6細胞株（其為大鼠肌原性細胞）。為根據用選自本發明化合物的代表性化合物處理來量測UBR1結合強度，將細胞等分至12孔盤中。將細胞另外培養24小時以便完全附著至盤的表面。在單獨用化合物（5微莫耳）處理24小時之後收集細胞以確認化合物是否增加UBR1結合。為自所收集的細胞提取蛋白質，將50微升的裂解緩衝液（20 mM Tris（pH 7.4）、150 mM NaCl、1% Triton-X-100、2 mM NaF、2 mM EDTA、2 mM b-甘油磷酸鹽、5 mM原釩酸鈉、1 mM PMSF、抗纖維蛋白溶酶肽、抑肽酶）注射至各樣品中，且裂解細胞。基於所量測的總蛋白質濃度，將樣品緩衝液添加至各樣品中且使混合物在100℃下反應5分鐘。在自完全反應的樣品取出5微升且等分至丙烯醯胺凝膠的各孔中之後，執行免疫墨點法，且實驗結果示出在[圖3]中。對於免疫墨點法，根據三個或超過三個獨立實驗示意性展示一代表性實驗。
參看圖3，可確認ACTA1的含量藉由化合物1、化合物2進一步增加。亦即，可確認在使用根據本發明的化合物處理的情況下，肌肉內蛋白質ACTA1的降解藉由與UBR1結合來抑制。實例 2-4 使用 MST 量測 UBR1 與化合物之間是否存在結合 1）製備UBR1蛋白質
將對應於人類UBR1的UBR盒的Gln97-Pro168部分（UniProt ID: Q8IWV7）選殖至經修飾的表現載體中，且隨後在大腸桿菌（E.coli）中表現。在使用親和力層析法之後，藉由蛋白酶移除標記，且隨後將Gly-His-Met添加至N末端。在執行離子層析法之後，在10 mM NaCl、20 mM Tris-HCl、2 mM β-巰基乙醇以及pH 7.5的緩衝液組成物中使用凝膠過濾層析法純化UBR1的最終UBR盒蛋白。 2）UBR1 UBR盒蛋白標記
Monolith蛋白標記套組RED-NHS第2代的染料（目錄號MO-L011）具有與一級胺（離胺酸殘基）形成共價鍵的NHS-酯基團。此染料針對配備有RED偵測器的Monolith系列裝置最佳化。根據所提供方案使用此套組來標記純化的UBR1 UBR盒蛋白。 3）使用MST量測UBR1與配體之間是否存在結合
熱泳指代粒子由於溫度梯度而移動的現象。存在於高溫區中的粒子具有比存在於低溫區中的粒子更大的動能，且與具有更大能量的周圍粒子更頻繁地碰撞。因此，粒子自高溫區移動至低溫區。
蛋白質的熱泳通常與蛋白質配體複合物的熱泳不同。此是因為配體的結合改變其大小、電荷以及溶合能。此外，即使配體結合不明顯地改變蛋白質的大小及電荷，MST亦可偵測由配體結合造成的蛋白分子的溶劑熵的變化。因此，使用MST來量測UBR1 UBR盒蛋白與配體化合物的結合，且確認所提供的配體與UBR1 UBR盒結合。
無
圖1示出使用免疫墨點法確認肌肉肌動蛋白是否為Arg/N-降解決定子路徑基質的實驗結果。 圖2示出使用活體外轉錄/轉譯法確認R-nsp4的表現是否根據與化合物（化合物1、化合物2）的UBR1的結合的實驗結果。 圖3示出使用免疫墨點法確認化合物（化合物1、化合物2）是否抑制肌肉細胞中的肌動蛋白的降解的實驗結果。 圖4及圖5示出藉由微尺度熱泳（MST）結合化合物1及化合物2的結果。

Claims (4)

  1. 一種化合物，具有式1的結構： [式1]
    Figure 03_image011
    或其鹽， 其中A1 為CH3 或NH2 。
  2. 一種用於抑制UBR盒結構域基質結合的組成物， 其中所述組成物包括如請求項1所述的化合物或其鹽。
  3. 一種用於治療UBR相關疾病的醫藥組成物， 其中所述組成物包括如請求項1所述的化合物或其醫藥學上可接受的鹽。
  4. 如請求項3所述的用於治療UBR相關疾病的醫藥組成物， 其中所述UBR相關疾病包括由肌肉萎縮症（貝克爾（Becker）、先天性、杜興氏（Duchenne）、遠端型、埃-德二氏（Emery-Dreifuss）、面肩臂、肢帶型、肌強直性、眼咽部（ocuophargyngeal））引起的肌肉損失；由肌肉損失或降解介導的肌肉萎縮疾病，包含肌肉減少症或癌症惡病質；由過度的蛋白質降解引起的疾病，包含脂肪肉瘤、囊腫纖維化、約翰遜-布利澤德症候群（Johanson-Blizzard syndrome）、阻塞性尿路疾病（尿道阻塞序列）；自體免疫性胰臟炎；或與UBR盒及UBR蛋白相關的已知疾病，包含尤塞氏症候群（Usher syndrome）。
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