应用二价“点击”方法靶向酪氨酸- dna磷酸二酯酶1 (TDP1)。

IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Xue Zhi Zhao, Wenjie Wang, Md Rasel Al Mahmud, Keli Agama, Yves Pommier, Terrence R Burke
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引用次数: 0

摘要

虽然抑制DNA修复酶酪氨酸-DNA磷酸二酯酶1 (TDP1)与拓扑异构酶I型(TOP1)抑制剂在抗癌治疗中协同作用,但TDP1抑制剂的开发一直具有很高的挑战性。这可能是由于TDP1催化位点的开放和浅的性质,以及必须与一个大而高度延伸的底物竞争。通过引入蛋白质降解剂选择性消除TDP1的能力,化学生物学家研究TDP1的工具箱可以得到显著增强。我们目前的工作是从苯基咪唑吡啶基TDP1抑制剂开始的,这些抑制剂以前是由小分子微阵列(SMMs)开发的。利用结合TDP1的铅抑制剂的晶体结构,我们设计并合成了一系列靶向二价蛋白水解嵌合体(PROTACs)。我们目前的工作重点是探索允许安装E3连接酶靶向功能的合成方法,同时保留TDP1的结合。我们采用铜催化叠氮化物-炔环加成(CuAAC)“点击”反应将PROTAC成分与含1,2,3-三唑的连接物组装在一起。通过添加相对较大的连接子和e3靶向部分,我们保留了抑制TDP1的能力。以tdp1为导向的PROTACS的成功开发将产生一种新的治疗类别,可以潜在地提高TOP1抑制剂的疗效和选择性,包括那些用作抗体药物偶联物(adc)有效载荷的TOP1抑制剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Application of a bivalent "click" approach to target tyrosyl-DNA phosphodiesterase 1 (TDP1).

Although inhibiting the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) synergizes with topoisomerase type I (TOP1) inhibitors in anticancer therapy, development of TDP1 inhibitors has been highly challenging. This may be due to the open and shallow nature of the TDP1 catalytic site and the necessity of competing with a large and highly extended substrate. The toolbox available to chemical biologists for studying TDP1 could be significantly enhanced by introducing the ability to selectively eliminate TDP1 using protein degraders. Our current work starts from phenyl imidazopyridine-based TDP1 inhibitors previously developed from small molecule microarrays (SMMs). Using crystal structures of lead inhibitors bound to TDP1, we designed and synthesized a series of bivalent proteolysis-targeting chimeras (PROTACs). The focus of our current work is to explore synthetic approaches that permit installation of E3 ligase-targeting functionality, while retaining the TDP1 binding. We employed copper-catalyzed azide-alkyne cycloaddition (CuAAC) "click" reactions to assemble PROTAC constituents with 1,2,3-triazole-containing linkers. With the addition of the relatively large parts of the linkers and E3-targeting moieties, we retained the ability to inhibit TDP1. The successful development of TDP1-directed PROTACS would yield a new therapeutic class that could potentially enhance the efficacy and selectivity of TOP1 inhibitors including those used as payloads in antibody drug conjugates (ADCs).

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来源期刊
CiteScore
5.80
自引率
2.40%
发文量
129
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