High-Affinity Probes for Androgen Receptor Imaging: From Cells and In Silico Modeling to Whole-Body Fluorescent Applications.

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-07-25 DOI:10.1021/acs.jmedchem.5c00836

Saheed A Ayodeji,Yaroslav Balytskyi,Destina Unaegbu,Allison Ingman,Christopher V Kelly,Sheryl Roberts

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Abstract

Castrate-resistant prostate cancer (CRPC) is driven by androgen receptor (AR) signaling. Imaging tools to monitor AR signaling dynamics are a high-priority goal. Here, we introduce ARi-FL, a series of visible- and near-infrared fluorescent AR inhibitors. Based on an aryloxy cyclohexane scaffold, a neolinker enabled amine-based conjugation to fluorophores. ARi-FL showed potent AR inhibition (IC50 ∼ 13 nM) and allowed visualization of cytoplasmic AR, correlating with AR-expressing cells, which were blockable with excess unlabeled ligand. In vivo and ex vivo studies in human prostate cancer models confirmed ARi-FL localization in AR-positive tumors. In silico modeling across wild-type (WT) and clinically relevant AR mutants (F877L, T878A, H875Y, W742C, and F877L/T878A) revealed nanomolar binding affinities (Kd ∼ 1-2 nM), consistent with experimental results. ARi-FL probes demonstrated high selectivity, practical yields, and stability. Taken together, ARi-FL offers a chemical imaging platform for noninvasive AR tracking with applications for studying resistance mechanisms of AR and guiding treatment decisions.

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高亲和探针雄激素受体成像：从细胞和硅建模到全身荧光应用。

去势抵抗性前列腺癌（CRPC）是由雄激素受体（AR）信号驱动的。监控AR信号动态的成像工具是一个高度优先的目标。在这里，我们介绍ARi-FL，一系列可见和近红外荧光AR抑制剂。基于芳氧基环己烷支架，一种新的连接剂使胺基偶联到荧光团。ARi-FL显示出有效的AR抑制作用（IC50 ~ 13 nM），并允许细胞质AR可视化，与AR表达细胞相关，这些细胞可被过量的未标记配体阻断。人前列腺癌模型的体内和离体研究证实了ar阳性肿瘤中ARi-FL的定位。野生型（WT）和临床相关的AR突变体（F877L、T878A、H875Y、W742C和F877L/T878A）的硅模型显示出纳米摩尔结合亲和力（Kd ~ 1-2 nM），与实验结果一致。ARi-FL探针具有高选择性、实用收率和稳定性。综上所述，ARi-FL为无创AR跟踪提供了一个化学成像平台，可用于研究AR的耐药机制和指导治疗决策。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.