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Development of a High-Throughput Screening Assay for Small-Molecule Inhibitors of Androgen Receptor Splice Variants
ASSAY and Drug Development Technologies ( IF 1.8 ) Pub Date : 2022-04-18 , DOI: 10.1089/adt.2021.128
Amy E Monaghan 1 , Alison Porter 2 , Irene Hunter 1 , Angus Morrison 2 , Stuart P McElroy 2 , Iain J McEwan 1
Affiliation  

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.

中文翻译:

雄激素受体剪接变异体小分子抑制剂高通量筛选方法的开发

雄激素受体 (AR) 在前列腺癌 (PCa) 进展中的作用已得到充分确立,并且竞争性抑制 AR 配体结合域 (LBD) 已成为晚期和转移性疾病的抗雄激素治疗的中流砥柱。然而,此类药物的功效通常受到耐药性出现的限制,耐药性是通过点突变和缺乏 AR-LBD 的受体剪接变体介导的。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)对于基因调控和参与蛋白质-蛋白质相互作用都很重要。然而,由于域的内在无序结构,它作为治疗干预候选者的潜力被普遍忽视。在本文中,我们描述了一种基于功能性细胞的检测方法的设计和开发,旨在识别 AR-NTD 的小分子抑制剂。我们证明了该测定法对高通量筛选平台的适用性,并验证了从 PCa 细胞中的小型靶向库筛选中出现的两个初始命中。
更新日期:2022-04-21
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