Comparative Evaluation and Profiling of Chemical Tools for the Nuclear Hormone Receptor Family 2.

IF 4.9 Q1 CHEMISTRY, MEDICINAL
ACS Pharmacology and Translational Science Pub Date : 2025-03-14 Epub Date: 2025-02-20 DOI:10.1021/acsptsci.4c00719
Max Lewandowski, Romy Busch, Julian A Marschner, Daniel Merk
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引用次数: 0

Abstract

Nuclear receptors regulate transcription in response to ligand signals and enable the pharmacological control of gene expression. However, many nuclear receptors are still poorly explored and are not accessible to ligand-based target identification studies. In particular, most members of the NR2 family are among the least studied proteins of the class, and apart from the retinoid X receptors (RXR), validated NR2 ligands are very rare. Here, we gathered the NR2 modulators reported in literature for comparative profiling in uniform test systems. Most candidate compounds displayed insufficient on-target activity or selectivity to be used as chemical tools for NR2 receptors underscoring the urgent need for further NR2 ligand development. Nevertheless, a small NR2 modulator set could be assembled for application in a chemogenomic fashion. There are 48 ligand-activated transcription factors in humans forming the superfamily of nuclear receptors (NRs, Figure 1a),1,2 which translate (endogenous) ligand signals into changes in gene expression patterns.3 The multifaceted roles of NRs span pivotal physiological processes, encompassing metabolism, inflammation, and cellular differentiation.4 Over decades, the NR1 and NR3 receptor families, including (steroid) hormone receptors and lipid sensors, have emerged as well-explored therapeutic targets of essential drugs like, for example, glucocorticoids as anti-inflammatory drugs, estrogen receptor modulators as contraceptives and anticancer agents, and PPAR agonists as oral antidiabetics.5-7 Despite this progress, a significant portion of the NR superfamily remains understudied, particularly within the NR2 family which comprises the hepatocyte nuclear factor-4 receptors (HNF4α/γ; NR2A1/2), the retinoid X receptors (RXRα/β/γ; NR2B1-3), the testicular receptors (TR2/4; NR2C1/2), the tailless-like receptors (TLX and PNR; NR2E1/3), and the COUP-TF-like receptors (COUP-TF1/2, V-erBA-related gene; NR2F1/2/6).8,9 Apart from RXR, all NR2 receptors are considered as orphan, and their ligands remain widely elusive. Therefore, chemical tools for most NR2 receptors are rare and poorly annotated posing an obstacle to target identification and validation studies. To enable chemogenomics on NR2 receptors and improve annotation, of the few available ligands, we gathered a scarce collection of NR2 modulators (agonists, antagonists, inverse agonists) for comparative evaluation and profiling. While the NR2B family (RXR) is well covered with high-quality ligands and a few early tools are available for NR2E1, we found the available ligands of the NR2A and NR2C families of insufficient quality to be used as chemical tools.

核激素受体家族化学工具的比较评价和分析2。
核受体根据配体信号调节转录,从而实现基因表达的药理学控制。然而,许多核受体仍然很少被探索,无法进行基于配体的靶标鉴定研究。特别是,NR2家族的大多数成员都是该类蛋白中研究最少的,除了类视黄醛X受体(RXR)外,验证的NR2配体非常罕见。在这里,我们收集了文献中报道的NR2调制器,用于在均匀测试系统中进行比较分析。大多数候选化合物的靶向活性或选择性不足以作为NR2受体的化学工具,这强调了进一步开发NR2配体的迫切需要。然而,一个小的NR2调节剂集可以组装应用于化学基因组学的方式。人类有48种配体激活的转录因子组成了核受体超家族(NRs,图1a),1,2,它们将(内源性)配体信号转化为基因表达模式的变化NRs在关键的生理过程中起着多方面的作用,包括代谢、炎症和细胞分化几十年来,NR1和NR3受体家族,包括(类固醇)激素受体和脂质传感器,已经成为基本药物的治疗靶点,例如,作为消炎药的糖皮质激素,作为避孕药和抗癌剂的雌激素受体调节剂,以及作为口服降糖药的PPAR激动剂。尽管取得了这些进展,NR超家族的很大一部分仍未得到充分研究,特别是在NR2家族中,包括肝细胞核因子-4受体(HNF4α/γ;NR2A1/2),类视黄醇X受体(RXRα/β/γ;NR2B1-3),睾丸受体(TR2/4;nr2c2 /2),无尾样受体(TLX和PNR;NR2E1/3)和coup - tf样受体(COUP-TF1/2, v - erba相关基因;NR2F1/2/6)。8,9除RXR外,所有的NR2受体都被认为是孤儿受体,它们的配体仍然难以捉摸。因此,大多数NR2受体的化学工具很少,而且注释不充分,这对靶标鉴定和验证研究构成了障碍。为了能够对NR2受体进行化学基因组学研究,并改进对少数可用配体的注释,我们收集了少量的NR2调节剂(激动剂、拮抗剂、逆激动剂),用于比较评估和分析。虽然NR2B家族(RXR)被高质量的配体所覆盖,NR2E1也有一些早期的工具可用,但我们发现NR2A和NR2C家族的可用配体质量不足,无法用作化学工具。
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来源期刊
ACS Pharmacology and Translational Science
ACS Pharmacology and Translational Science Medicine-Pharmacology (medical)
CiteScore
10.00
自引率
3.30%
发文量
133
期刊介绍: ACS Pharmacology & Translational Science publishes high quality, innovative, and impactful research across the broad spectrum of biological sciences, covering basic and molecular sciences through to translational preclinical studies. Clinical studies that address novel mechanisms of action, and methodological papers that provide innovation, and advance translation, will also be considered. We give priority to studies that fully integrate basic pharmacological and/or biochemical findings into physiological processes that have translational potential in a broad range of biomedical disciplines. Therefore, studies that employ a complementary blend of in vitro and in vivo systems are of particular interest to the journal. Nonetheless, all innovative and impactful research that has an articulated translational relevance will be considered. ACS Pharmacology & Translational Science does not publish research on biological extracts that have unknown concentration or unknown chemical composition. Authors are encouraged to use the pre-submission inquiry mechanism to ensure relevance and appropriateness of research.
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