Tan M H Eileen, Li Jun, Xu H Eric, Melcher Karsten, Yong Eu-leong
1] Department of Obstetrics & Gynecology, National University Hospital, Yong Loo Lin School of Medicine, National University of Singapore, Singapore [2] Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, MI 49503, USA.
Department of Obstetrics & Gynecology, National University Hospital, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Acta Pharmacol Sin. 2015 Jan;36(1):3-23. doi: 10.1038/aps.2014.18. Epub 2014 Jun 9.
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.
雄激素和雄激素受体（AR）在男性表型的表达中起关键作用。几种疾病，如雄激素不敏感综合征（AIS）和前列腺癌，都与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作用的药物进行雄激素阻断可抑制前列腺癌的生长。然而，由于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在2至3年后出现。在CRPC中，功能性AR仍然是关键调节因子。早期研究集中在AR的功能结构域及其在病理学中的关键作用。AR DNA结合结构域（DBD）和配体结合结构域（LBD）结构的阐明为理解该受体的功能提供了新框架，并导致了用于治疗前列腺癌的合理药物设计的发展。本文概述了雄激素受体的结构和活性、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被或可用于药物发现。
