靶向DNA修复酶APE1在癌症治疗中的应用

Debanu Das, P. Pellicena, M. Duncton, David Wilson, M. Georgiadis, A. Deacon
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引用次数: 0

摘要

癌细胞通过上调DNA损伤反应(DDR)来应对DNA损伤的增加。碱基切除修复(BER)途径通过多种酶的作用来纠正单个DNA碱基的损伤,包括中心主角,无嘌呤/无嘧啶内切酶1 (APE1)。大量研究表明,APE1水平升高与人类肿瘤细胞生长、迁移和耐药增强以及患者生存率降低有关。APE1与20多种人类癌症有关,这使得它成为开发抗癌疗法的一个有吸引力的靶点。尽管付出了巨大的努力,但目前还没有临床的APE1核酸内切酶抑制剂。我们使用新开发的基于高通量蛋白质x射线晶体学的片段筛选来获得阻断APE1功能的分子设计的起点。从专有的片段库开始,我们获得了高质量的片段结合晶体结构,显示了化学物质和命中位置的多样性,代表了APE1与药物样分子结合的第一个实验3D结构,从而解决了抑制剂开发路径中的主要瓶颈。这种独特的先导发现活动的实施促进了开发APE1抑制剂的三种独立策略,包括(i)片段生长和在核酸内切酶位点结合的命中的细化;(ii)将结合到不同但近端位置的片段连接起来,以及(iii)使用片段设计钩子,用于靶向蛋白质降解(TPD)策略。我们正在结合计算化学和药物化学、结构生物学、生化和生物物理学研究,并将讨论我们在实现这些目标方面的进展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeting the DNA repair enzyme APE1 in cancer therapy
Cancer cells respond to increases in DNA damage by upregulating their DNA damage response (DDR). The base excision repair (BER) pathway corrects damage to single DNA bases through the action of multiple enzymes, including the central protagonist, apurinic/apyrimidinic endonuclease 1 (APE1). Numerous studies have shown association between increased APE1 levels and enhanced growth, migration, and drug resistance in human tumor cells, as well as with decreased patient survival. APE1 has been implicated in over 20 human cancers, making this an attractive target for developing anticancer therapies. Despite intensive effort, there are currently no clinical endonuclease inhibitors of APE1. We have used a newly developed high-throughput protein X-ray crystallography-based fragment screen to obtain starting points for the design of molecules to block APE1 function. Starting with a proprietary fragment library, we obtained high quality fragment-bound crystal structures showing diversity of chemical matter and hit location, representing the first experimental 3D structures of APE1 bound to drug-like molecules, thereby resolving a primary bottleneck in the path to inhibitor development. The implementation of this unique lead discovery campaign has facilitated three independent strategies toward the development of APE1 inhibitors, including (i) fragment growing and elaboration of hits bound at the endonuclease site; (ii) linking of fragments bound to distinct but proximally located sites, and (iii) use of fragments for the design of hooks to use in targeted protein degradation (TPD) strategies. We are using a combination of computational and medicinal chemistry, structural biology, and biochemical and biophysical studies and will discuss our progress towards these goals.
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