Genome Sciences, BC Cancer and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
Expert Opin Drug Discov. 2020 May;15(5):551-560. doi: 10.1080/17460441.2020.1732920. Epub 2020 Feb 26.
: Intrinsically disordered proteins (IDPs) and regions (IDRs) lack stable three-dimensional structure making drug discovery challenging. A validated therapeutic target for diseases such as prostate cancer is the androgen receptor (AR) which has a disordered amino-terminal domain (NTD) that contains all of its transcriptional activity. Drug discovery against the AR-NTD is of intense interest as a potential treatment for disease such as advanced prostate cancer that is driven by truncated constitutively active splice variants of AR that lack the C-terminal ligand-binding domain (LBD).: This article presents an overview of the relevance of AR and its intrinsically disordered NTD as a drug target. AR structure and approaches to blocking AR transcriptional activity are discussed. The discovery of small molecules, including the libraries used, proven binders to the AR-NTD, and site of interaction of these small molecules in the AR-NTD are presented along with discussion of the Phase I clinical trial.: The lack of drugs in the clinic that directly bind IDPs/IDRs reflects the difficulty of targeting these proteins and obtaining specificity. However, it may also point to an inappropriateness of too closely borrowing concepts and resources from drug discovery to folded proteins.
: 无规则蛋白质（IDPs）和区域（IDRs）缺乏稳定的三维结构，这使得药物发现具有挑战性。雄激素受体（AR）是前列腺癌等疾病的一个经过验证的治疗靶点，它具有无规则的氨基末端结构域（NTD），其中包含其所有的转录活性。针对 AR-NTD 的药物发现是一个很有意义的研究方向，因为它可能成为治疗疾病的一种方法，例如由缺乏 C 端配体结合域（LBD）的 AR 截断组成型激活剪接变体驱动的晚期前列腺癌。: 本文概述了 AR 及其无规则 NTD 作为药物靶点的相关性。讨论了 AR 的结构和阻断 AR 转录活性的方法。本文介绍了小分子的发现，包括用于构建文库的小分子、已证明与 AR-NTD 结合的配体，以及这些小分子在 AR-NTD 中的相互作用部位，并讨论了这些小分子在 AR-NTD 中的相互作用部位的临床前研究。: 临床上缺乏直接与 IDPs/IDRs 结合的药物反映了靶向这些蛋白质并获得特异性的困难。然而，这也可能表明，过于密切地借鉴针对折叠蛋白质的药物发现的概念和资源并不合适。
