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10.1210/me.2014-1069

http://scihub22266oqcxt.onion/10.1210/me.2014-1069
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C4075162!4075162!24850414
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suck abstract from ncbi


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pmid24850414      Mol+Endocrinol 2014 ; 28 (7): 1194-206
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  • Research Resource: Modulators of Glucocorticoid Receptor Activity Identified by a New High-Throughput Screening Assay #MMPMID24850414
  • Blackford JA; Brimacombe KR; Dougherty EJ; Pradhan M; Shen M; Li Z; Auld DS; Chow CC; Austin CP; Simons SS
  • Mol Endocrinol 2014[Jul]; 28 (7): 1194-206 PMID24850414show ga
  • 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 (Amax) and EC50 (the position of the dexamethasone dose-response curve). Upon screening 1280 chemicals, 10 with the greatest changes in the absolute value of Amax or EC50 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.
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