NR4A1 Ligands as Potent Inhibitors of Breast Cancer Cell and Tumor Growth
Nuclear receptor 4A1 (NR4A1, Nur77, TR3) is more highly expressed in breast and solid tumors compared to non-tumor tissues and is a pro-oncogenic factor in solid tumor-derived cancers. NR4A1 regulates cancer cell growth, survival, migration, and invasion, and bis-indole-derived compounds (CDIMs) tha...
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doaj-2267074735a94921a7d063362099c53f2021-06-01T01:35:09ZengMDPI AGCancers2072-66942021-05-01132682268210.3390/cancers13112682NR4A1 Ligands as Potent Inhibitors of Breast Cancer Cell and Tumor GrowthKeshav Karki0Kumaravel Mohankumar1Abigail Schoeller2Gregory Martin3Rupesh Shrestha4Stephen Safe5Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USADepartment of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USADepartment of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USADepartment of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USADepartment of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USADepartment of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USANuclear receptor 4A1 (NR4A1, Nur77, TR3) is more highly expressed in breast and solid tumors compared to non-tumor tissues and is a pro-oncogenic factor in solid tumor-derived cancers. NR4A1 regulates cancer cell growth, survival, migration, and invasion, and bis-indole-derived compounds (CDIMs) that bind NR4A1 act as antagonists and inhibit tumor growth. Preliminary structure-binding studies identified 1,1-bis(3′-indolyl)-1-(3,5-disubstitutedphenyl)methane analogs as NR4A1 ligands with low K<sub>D</sub> values; we further investigated the anticancer activity of the four most active analogs (K<sub>D</sub>’s ≤ 3.1 µM) in breast cancer cells and in athymic mouse xenograft models. The treatment of MDA-MB-231 and SKBR3 breast cancer cells with the 3-bromo-5-methoxy, 3-chloro-5-trifluoromethoxy, 3-chloro-5-trifluoromethyl, and 3-bromo-5-trifluoromethoxy phenyl-substituted analogs decreased cell growth and the expression of epidermal of growth factor receptor (EGFR), hepatocyte growth factor receptor (cMET), and PD-L1 as well as inhibited mTOR phosphorylation. In addition, all four compounds inhibited tumor growth in athymic nude mice bearing MDA-MB-231 cells (orthotopic) at a dose of 1 mg/kg/d, which was not accompanied by changes in body weight. These 3,5-disubstituted analogs were the most potent CDIM/NR4A1 ligands reported and are being further developed for clinical applications.https://www.mdpi.com/2072-6694/13/11/2682NR4A1breast cancerligandsinhibition |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Keshav Karki Kumaravel Mohankumar Abigail Schoeller Gregory Martin Rupesh Shrestha Stephen Safe |
spellingShingle |
Keshav Karki Kumaravel Mohankumar Abigail Schoeller Gregory Martin Rupesh Shrestha Stephen Safe NR4A1 Ligands as Potent Inhibitors of Breast Cancer Cell and Tumor Growth Cancers NR4A1 breast cancer ligands inhibition |
author_facet |
Keshav Karki Kumaravel Mohankumar Abigail Schoeller Gregory Martin Rupesh Shrestha Stephen Safe |
author_sort |
Keshav Karki |
title |
NR4A1 Ligands as Potent Inhibitors of Breast Cancer Cell and Tumor Growth |
title_short |
NR4A1 Ligands as Potent Inhibitors of Breast Cancer Cell and Tumor Growth |
title_full |
NR4A1 Ligands as Potent Inhibitors of Breast Cancer Cell and Tumor Growth |
title_fullStr |
NR4A1 Ligands as Potent Inhibitors of Breast Cancer Cell and Tumor Growth |
title_full_unstemmed |
NR4A1 Ligands as Potent Inhibitors of Breast Cancer Cell and Tumor Growth |
title_sort |
nr4a1 ligands as potent inhibitors of breast cancer cell and tumor growth |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2021-05-01 |
description |
Nuclear receptor 4A1 (NR4A1, Nur77, TR3) is more highly expressed in breast and solid tumors compared to non-tumor tissues and is a pro-oncogenic factor in solid tumor-derived cancers. NR4A1 regulates cancer cell growth, survival, migration, and invasion, and bis-indole-derived compounds (CDIMs) that bind NR4A1 act as antagonists and inhibit tumor growth. Preliminary structure-binding studies identified 1,1-bis(3′-indolyl)-1-(3,5-disubstitutedphenyl)methane analogs as NR4A1 ligands with low K<sub>D</sub> values; we further investigated the anticancer activity of the four most active analogs (K<sub>D</sub>’s ≤ 3.1 µM) in breast cancer cells and in athymic mouse xenograft models. The treatment of MDA-MB-231 and SKBR3 breast cancer cells with the 3-bromo-5-methoxy, 3-chloro-5-trifluoromethoxy, 3-chloro-5-trifluoromethyl, and 3-bromo-5-trifluoromethoxy phenyl-substituted analogs decreased cell growth and the expression of epidermal of growth factor receptor (EGFR), hepatocyte growth factor receptor (cMET), and PD-L1 as well as inhibited mTOR phosphorylation. In addition, all four compounds inhibited tumor growth in athymic nude mice bearing MDA-MB-231 cells (orthotopic) at a dose of 1 mg/kg/d, which was not accompanied by changes in body weight. These 3,5-disubstituted analogs were the most potent CDIM/NR4A1 ligands reported and are being further developed for clinical applications. |
topic |
NR4A1 breast cancer ligands inhibition |
url |
https://www.mdpi.com/2072-6694/13/11/2682 |
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