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基于对硝基苯磺酰胺模板的新型潜在 ERRα 反向激动剂系列化合物的发现，可用于三阴性乳腺癌。

The discovery of a novel series of potential ERRα inverse agonists based on p-nitrobenzenesulfonamide template for triple-negative breast cancer .

机构信息

School of Chemistry and Chemical Engineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, P. R. China.

Department of Pharmacy, Huashan Hospital, Fudan University, Shanghai, P. R. China.

出版信息

J Enzyme Inhib Med Chem. 2022 Dec;37(1):125-134. doi: 10.1080/14756366.2021.1995728.

DOI:10.1080/14756366.2021.1995728
PMID:34894977
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8667933/
Abstract

Oestrogen related receptor α participated in the regulation of oxidative metabolism and mitochondrial biogenesis, and was overexpressed in many cancers including triple-negative breast cancer. A set of new ERRα inverse agonists based on p-nitrobenzenesulfonamide template were discovered and compound with high potent activity (IC = 0.80 μM) could significantly inhibit the transcription of ERRα-regulated target genes. By regulating the downstream signalling pathway, compound could suppress the migration and invasion of the ER-negative MDA-MB-231 cell line. Furthermore, compound demonstrated a significant growth suppression of breast cancer xenograft tumours (inhibition rate 23.58%). The docking results showed that compound could form hydrogen bonds with Glu331 and Arg372 in addition to its hydrophobic interaction with ligand-binding domain. Our data implied that compound represented a novel and effective ERRα inverse agonist, which had broad application prospects in the treatment of triple-negative breast cancer.

摘要

雌激素相关受体α（ERRα）参与氧化代谢和线粒体生物发生的调节，在许多癌症中过表达，包括三阴性乳腺癌。一组基于对硝基苯磺酰胺模板的新型 ERRα反向激动剂被发现，其中具有高活性的化合物 （IC = 0.80 μM）可显著抑制 ERRα 调节的靶基因的转录。通过调节下游信号通路，化合物 可抑制 ER 阴性 MDA-MB-231 细胞系的迁移和侵袭。此外，化合物 对乳腺癌异种移植瘤具有显著的生长抑制作用 （抑制率 23.58%）。对接结果表明，化合物 除了与配体结合域的疏水相互作用外，还可以与 Glu331 和 Arg372 形成氢键。我们的数据表明，化合物 代表了一种新型有效的 ERRα 反向激动剂，在治疗三阴性乳腺癌方面具有广阔的应用前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/b487027edd50/IENZ_A_1995728_F0009_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/2d60c613aa43/IENZ_A_1995728_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/603663c9a052/IENZ_A_1995728_F0002_C.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/e771f5b35808/IENZ_A_1995728_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/fed5d7cd874d/IENZ_A_1995728_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/7ec1930255e4/IENZ_A_1995728_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/0ea8b2eafcad/IENZ_A_1995728_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/b08ac080c9df/IENZ_A_1995728_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/c95934572f8f/IENZ_A_1995728_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/b487027edd50/IENZ_A_1995728_F0009_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/2d60c613aa43/IENZ_A_1995728_F0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/603663c9a052/IENZ_A_1995728_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/735137187968/IENZ_A_1995728_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/e771f5b35808/IENZ_A_1995728_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/fed5d7cd874d/IENZ_A_1995728_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/7ec1930255e4/IENZ_A_1995728_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/0ea8b2eafcad/IENZ_A_1995728_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/b08ac080c9df/IENZ_A_1995728_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/c95934572f8f/IENZ_A_1995728_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b03a/8667933/b487027edd50/IENZ_A_1995728_F0009_C.jpg

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Oncogene. 2019 Feb;38(7):950-964. doi: 10.1038/s41388-018-0579-3. Epub 2018 Nov 26.
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Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
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CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12.
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Indazole-based ligands for estrogen-related receptor α as potential anti-diabetic agents.基于吲唑的雌激素相关受体 α 配体作为潜在的抗糖尿病药物。
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