靶向雄激素受体N末构域抑制剂的研究现状与前景
Current Status and Future Prospects of Inhibitors Targeting the N-Terminal Domain of the Androgen Receptor
DOI: 10.12677/hjmce.2026.141005, PDF,   
作者: 向凤娇, 蔡江涛：浙江师范大学化学与材料科学学院，浙江 金华
关键词: AR-NTD；前列腺癌；雄激素受体抑制剂；治疗耐药；AR-NTD； Prostate Cancer； Androgen Receptor Inhibitors； Treatment Resistance
摘要: 前列腺癌是男性中最常见的恶性肿瘤之一，在发达国家的发病率极高。中国前列腺癌的年龄标准化发病率虽然仍低于西方发达国家，但是全球增长最快的地区之一。而转移性去势抵抗性前列腺(mCRPC)是导致前列腺癌患者死亡的最主要原因。雄激素受体(AR)与mCRPC的发生和发展密切相关，AR在其中起着至关重要的作用。AR的氮末端结构域(AR-NTD)是其发挥转录激活作用的关键区域，且该区域内的激活功能域AF-1在基因表达调控以及蛋白质间相互作用过程中扮演着极为重要的角色。因此，针对NTD的药物研发对治疗CRPC尤为重要。但是，NTD的内在无序性的药物的研发衍生出了一系列的挑战。与传统的、具有稳定三维结构的药物靶点不同，AR-NTD在其未与伴侣蛋白结合时，缺乏稳定的刚性结构，药物分子难以靶向该区域。然而，这也是一个极具潜力的方向，因为针对NTD的药物有望克服目前针对LBD的疗法所产生的耐药性，特别是对表达AR剪接变异体(如AR-V7)的去势抵抗性前列腺癌(CRPC)患者可能有效。本文综述了靶向AR-NTD抑制剂的研发进展、作用机制、各类抑制剂的研发情况、临床研究进展以及面临的挑战与未来展望，旨在为前列腺癌治疗药物的进一步研发提供参考。
Abstract: Prostate cancer is one of the most common malignant tumors among men, with a high incidence rate in developed countries. Although the age-standardized incidence rate of prostate cancer in China is still lower than that in western developed countries, it is one of the fastest-growing regions in the world. Metastatic Castration-Resistant Prostate Cancer is the leading cause of death in prostate cancer patients. The Androgen Receptor (AR) is closely related to the occurrence and development of mCRPC, and AR plays a crucial role in it. The Nitrogen Terminal Domain (AR-NTD) of AR is a key region for its transcriptional activation, and the activation domain AF-1 within this region plays an extremely important role in gene expression regulation and protein-protein interactions. Therefore, drug development for NTD is particularly important for the treatment of CRPC. However, the development of drugs with inherent disorder in NTDs has given rise to a series of challenges. Unlike traditional drug targets with stable three-dimensional structures, AR-NTD lacks a stable rigid structure when it is not bound to partner proteins, making it difficult for drug molecules to target this region. However, this is also a highly promising direction, as drugs targeting NTDs have the potential to overcome the resistance generated by current therapies for LBD, especially for Castration Resistant Prostate Cancer (CRPC) patients expressing AR splicing variants such as AR-V7. This article reviews the research and development progress, mechanism of action, development status of various inhibitors, clinical research progress, challenges and future prospects of targeted AR-NTD inhibitors, aiming to provide reference for further research and development of prostate cancer treatment drugs.
文章引用：向凤娇, 蔡江涛. 靶向雄激素受体N末构域抑制剂的研究现状与前景[J]. 药物化学, 2026, 14(1): 39-52. https://doi.org/10.12677/hjmce.2026.141005

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