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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
Published on: November 15, 2013
Drug screening to target nuclear orphan receptor NR4A2 for cancer therapeutics
Takefumi Komiya1,2, Satomi Yamamoto1, Anuradha Roy3
1Division of Medical Oncology, University of Kansas Medical Center, Fairway, KS, USA.
Background:
Our previous study suggested NR4A2, a subfamily member of orphan nuclear receptors, is essential for survival of human cancer cells such as mucoepidermoid carcinoma (MEC).
Methods:
We conducted high throughput drug screening for NR4A2 inhibitors as a novel therapeutic modality. Positive screening was performed using a luciferase reporter vector containing NR4A2 binding sequence, and a CRE-reporter control vector was used to eliminate false positives. In vitro assays for positive hits were conducted.
Results:
A total of 23 Food and Drug Administration (FDA) and 43 Life Science Library compounds were identified, including several epidermal growth factor inhibitors and Src inhibitors. Subsequent in vitro assays confirmed that identified compounds were preferentially active in NR4A2+ cancer cells. Several candidate compounds appeared to suppress NR4A2 via inhibition of p-ERK, whereas a novel compound KU0171309 may act as a more direct inhibitor.
Conclusions:
Further research should focus on homologue selectivity, in vivo activity, and definitively deciphering the mechanism of action of KU0171309.
Insights
Researchers screened for NR4A2 inhibitors to treat mucoepidermoid carcinoma (MEC). Several FDA-approved and novel compounds showed efficacy against NR4A2+ cancer cells, with KU0171309 as a promising direct inhibitor.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Nuclear receptor NR4A2 is crucial for human cancer cell survival, including mucoepidermoid carcinoma (MEC).
- NR4A2 represents a potential therapeutic target for cancer treatment.
Purpose of the Study:
- To identify novel therapeutic agents targeting NR4A2.
- To screen for NR4A2 inhibitors using high-throughput drug screening.
Main Methods:
- High-throughput screening utilizing a luciferase reporter assay for NR4A2 binding.
- Employing a CRE-reporter control vector to mitigate false positives.
- Conducting in vitro assays to validate positive hits.
Main Results:
- Identified 23 FDA-approved and 43 Life Science Library compounds as potential NR4A2 inhibitors.
- Confirmed preferential activity of identified compounds against NR4A2+ cancer cells in vitro.
- Observed suppression of NR4A2 via p-ERK inhibition by several compounds; KU0171309 identified as a potential direct inhibitor.
Conclusions:
- KU0171309 demonstrates potential as a direct NR4A2 inhibitor.
- Further investigation into homologue selectivity and in vivo activity of KU0171309 is warranted.
- Deciphering the precise mechanism of action for KU0171309 is a key future direction.
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