Discovery of RORγ Allosteric Fluorescent Probes and Their Application: Fluorescence Polarization, Screening, and Bioimaging,Journal of Medicinal Chemistry

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Discovery of RORγ Allosteric Fluorescent Probes and Their Application: Fluorescence Polarization, Screening, and Bioimaging
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-03-05 , DOI: 10.1021/acs.jmedchem.4c00058
Yan-Cheng Yu ₁ , Zhen-Jiang Tong ₁ , Xiao-Ting Liang ₁ , Jia-Zhen Wu ₁ , Yu-Jing Xu ₁ , Jing-Jing Wang ₁ , Meng-Yuan Zhang ₁ , Tian-Hua Wei ₁ , Jin Yang ₁ , Yi-Bo Wang ₁ , Qing-Xin Wang ₁ , Qing-Qing Li ₁ , Zixuan Wang ₁ , XueJiao Leng ₁ , Ning Ding ₁ , Xin Xue ₁ , Shan-Liang Sun ₁ , Nian-Guang Li ₁ , Xiao-Long Wang ₁

Affiliation

Retinoic acid receptor-related orphan receptor γ (RORγ) acts as a crucial transcription factor in Th17 cells and is involved in diverse autoimmune disorders. RORγ allosteric inhibitors have gained significant research focus as a novel strategy to inhibit RORγ transcriptional activity. Leveraging the high affinity and selectivity of RORγ allosteric inhibitor MRL-871 (1), this study presents the design, synthesis, and characterization of 11 allosteric fluorescent probes. Utilizing the preferred probe 12h, we established an efficient and cost-effective fluorescence polarization-based affinity assay for screening RORγ allosteric binders. By employing virtual screening in conjunction with this assay, 10 novel RORγ allosteric inhibitors were identified. The initial SAR studies focusing on the hit compound G381-0087 are also presented. The encouraging outcomes indicate that probe 12h possesses the potential to function as a powerful tool in facilitating the exploration of RORγ allosteric inhibitors and furthering understanding of RORγ function.

中文翻译：

RORγ变构荧光探针的发现及其应用：荧光偏振、筛选和生物成像

视黄酸受体相关孤儿受体 γ (RORγ) 作为 Th17 细胞中的关键转录因子，参与多种自身免疫性疾病。 RORγ 变构抑制剂作为抑制 RORγ 转录活性的新策略已获得重要的研究焦点。本研究利用 RORγ 变构抑制剂MRL-871 ( 1 ) 的高亲和力和选择性，介绍了 11 种变构荧光探针的设计、合成和表征。利用优选的探针12h ，我们建立了一种高效且经济的基于荧光偏振的亲和测定法，用于筛选 RORγ 变构结合剂。通过采用虚拟筛选与该测定相结合，鉴定出 10 种新型 RORγ 变构抑制剂。还介绍了针对热门化合物G381-0087 的初步 SAR 研究。令人鼓舞的结果表明，探针12h具有成为促进 RORγ 变构抑制剂探索和进一步了解 RORγ 功能的强大工具的潜力。

更新日期：2024-03-05

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