雄激素受体剪接变异体小分子抑制剂高通量筛选试验的建立。

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Accounts of Chemical Research Pub Date : 2022-04-01 Epub Date: 2022-03-23 DOI:10.1089/adt.2021.128
Amy E Monaghan, Alison Porter, Irene Hunter, Angus Morrison, Stuart P McElroy, Iain J McEwan
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引用次数: 2

摘要

雄激素受体(AR)在前列腺癌(PCa)进展中的作用已得到充分证实,竞争性抑制AR配体结合域(LBD)已成为晚期和转移性疾病抗雄激素治疗的主要手段。然而,这些药物的疗效往往受到耐药性的限制,耐药性是通过缺乏AR-LBD的点突变和受体剪接变异体介导的。因此,恶性、去势抵抗性疾病患者的预后仍然很差。AR的氨基末端结构域(NTD)已被证明对AR功能至关重要。它的模块化激活功能(AF-1)对基因调控和参与蛋白-蛋白相互作用都很重要。然而,由于该结构域的内在无序结构,其作为治疗干预的候选物的潜力通常被忽视。在这篇文章中,我们描述了一种功能性细胞检测的设计和开发,旨在识别AR-NTD的小分子抑制剂。我们证明了该分析在高通量筛选平台上的适用性,并验证了在PCa细胞中从一个小的、靶向的文库筛选中出现的两个初始命中。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Development of a High-Throughput Screening Assay for Small-Molecule Inhibitors of Androgen Receptor Splice Variants.

Development of a High-Throughput Screening Assay for Small-Molecule Inhibitors of Androgen Receptor Splice Variants.

Development of a High-Throughput Screening Assay for Small-Molecule Inhibitors of Androgen Receptor Splice Variants.

Development of a High-Throughput Screening Assay for Small-Molecule Inhibitors of Androgen Receptor Splice Variants.

The role of the androgen receptor (AR) in the progression of prostate cancer (PCa) is well established and competitive inhibition of AR ligand binding domain (LBD) has been the mainstay of antiandrogen therapies for advanced and metastatic disease. However, the efficacy of such drugs is often limited by the emergence of resistance, mediated through point mutations and receptor splice variants lacking the AR-LBD. As a result, the prognosis for patients with malignant, castrate-resistant disease remains poor. The amino terminal domain (NTD) of the AR has been shown to be critical for AR function. Its modular activation function (AF-1) is important for both gene regulation and participation in protein-protein interactions. However, due to the intrinsically disordered structure of the domain, its potential as a candidate for therapeutic intervention has been generally overlooked. In this article, we describe the design and development of a functional cell-based assay aimed at identifying small-molecule inhibitors of the AR-NTD. We demonstrate the suitability of the assay for high-throughput screening platforms and validate two initial hits emerging from a small, targeted, library screen in PCa cells.

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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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