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Mol Endocrinol. 2014 Jul;28(7):1194-206. doi: 10.1210/me.2014-1069. Epub 2014 May 21.

Research resource: modulators of glucocorticoid receptor activity identified by a new high-throughput screening assay.

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Steroid Hormones Section (J.A.B., E.J.D., M.P., S.S.S.), Laboratory of Endocrinology and Receptor Biology, and Laboratory of Biological Modeling (C.C.C.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892; and National Center for Advancing Translational Sciences (K.R.B., M.S., Z.L., D.S.A., C.P.A.), National Institutes of Health, Rockville, Maryland 20892.


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.

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