Research resource : modulators of glucocorticoid receptor activity identified by a new high-throughput screening assay
Glucocorticoid steroids affect almost every type of tissue and thus are widely used to treat a variety of human pathological conditions. However, the severity of numerous side effects limits the frequency and duration of glucocorticoid treatments. Of the numerous approaches to control off-target responses to glucocorticoids, small molecules and pharmaceuticals offer several advantages. Here we describe a new, extended high-throughput screen in intact cells to identify small molecule modulators of dexamethasone-induced glucocorticoid receptor (GR) transcriptional activity. The novelty of this assay is that it monitors changes in both GR maximal activity (A(max)) and EC(50) (the position of the dexamethasone dose-response curve). Upon screening 1280 chemicals, 10 with the greatest changes in the absolute value of A(max) or EC(50) were selected for further examination. Qualitatively identical behaviors for 60% to 90% of the chemicals were observed in a completely different system, suggesting that other systems will be similarly affected by these chemicals. Additional analysis of the 10 chemicals in a recently described competition assay determined their kinetically defined mechanism and site of action. Some chemicals had similar mechanisms of action despite divergent effects on the level of the GR-induced product. These combined assays offer a straightforward method of identifying numerous new pharmaceuticals that can alter GR transactivation in ways that could be clinically useful.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2014 |
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| Erschienen: |
2014 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:28 |
|---|---|
| Enthalten in: |
Molecular endocrinology (Baltimore, Md.) - 28(2014), 7 vom: 17. Juli, Seite 1194-206 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Blackford, John A [VerfasserIn] |
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| Links: |
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| Themen: |
147336-22-9 |
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| Anmerkungen: |
Date Completed 16.04.2015 Date Revised 21.10.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1210/me.2014-1069 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM238457168 |
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| 245 | 1 | 0 | |a Research resource |b modulators of glucocorticoid receptor activity identified by a new high-throughput screening assay |
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| 500 | |a Date Revised 21.10.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Glucocorticoid steroids affect almost every type of tissue and thus are widely used to treat a variety of human pathological conditions. However, the severity of numerous side effects limits the frequency and duration of glucocorticoid treatments. Of the numerous approaches to control off-target responses to glucocorticoids, small molecules and pharmaceuticals offer several advantages. Here we describe a new, extended high-throughput screen in intact cells to identify small molecule modulators of dexamethasone-induced glucocorticoid receptor (GR) transcriptional activity. The novelty of this assay is that it monitors changes in both GR maximal activity (A(max)) and EC(50) (the position of the dexamethasone dose-response curve). Upon screening 1280 chemicals, 10 with the greatest changes in the absolute value of A(max) or EC(50) were selected for further examination. Qualitatively identical behaviors for 60% to 90% of the chemicals were observed in a completely different system, suggesting that other systems will be similarly affected by these chemicals. Additional analysis of the 10 chemicals in a recently described competition assay determined their kinetically defined mechanism and site of action. Some chemicals had similar mechanisms of action despite divergent effects on the level of the GR-induced product. These combined assays offer a straightforward method of identifying numerous new pharmaceuticals that can alter GR transactivation in ways that could be clinically useful | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Intramural | |
| 650 | 7 | |a Glucocorticoids |2 NLM | |
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| 700 | 1 | |a Brimacombe, Kyle R |e verfasserin |4 aut | |
| 700 | 1 | |a Dougherty, Edward J |e verfasserin |4 aut | |
| 700 | 1 | |a Pradhan, Madhumita |e verfasserin |4 aut | |
| 700 | 1 | |a Shen, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zhuyin |e verfasserin |4 aut | |
| 700 | 1 | |a Auld, Douglas S |e verfasserin |4 aut | |
| 700 | 1 | |a Chow, Carson C |e verfasserin |4 aut | |
| 700 | 1 | |a Austin, Christopher P |e verfasserin |4 aut | |
| 700 | 1 | |a Simons, S Stoney |c Jr |e verfasserin |4 aut | |
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