Androgen receptor: structure, role in prostate cancer and drug discovery.
Androgen receptor: structure, role in prostate cancer and drug discovery.
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DOI：
10.1038/aps.2014.18
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发表时间：
2015-01
影响因子：
8.2
通讯作者：
Yong EL
中科院分区：
文献类型：
--
作者：
Tan MH;Li J;Xu HE;Melcher K;Yong EL
雄激素和雄激素受体（AR）在男性表型的表达中发挥着关键作用。雄激素不敏感综合征 (AIS) 和前列腺癌等多种疾病与 AR 功能的改变有关。事实上，通过阻止雄激素产生和/或阻断 AR 作用的药物来阻断雄激素可以抑制前列腺癌的生长。然而，随着患者发展为去势抵抗性前列腺癌（CRPC），对这些药物的耐药性通常会在 2-3 年后出现。在 CRPC 中，功能性 AR 仍然是关键的调节器。早期的研究集中在 AR 的功能域及其在病理学中的关键作用。 AR DNA结合域（DBD）和配体结合域（LBD）结构的阐明为理解该受体的功能提供了新的框架，并导致了治疗前列腺癌的合理药物设计的发展。本文提供了雄激素受体结构和活性、其在前列腺癌中的作用以及结构信息和高通量筛选如何已经或可以用于药物发现的概述。
Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2–3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein.