Small-molecule profiling for steroid receptor activity using a universal steroid receptor reporter assay

Unlike FKBP52, the FK1 domain of FKBP51 exhibits microsecond–millisecond conformational dynamics in the β3 bulge and the β4–β5 loop, known sites of protein signalling interactions. Swapping residue 119 yields altered conformational dynamics in a pattern reminiscent of reported modulations in steroid receptor activity.

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Regulation of Nuclear Receptor Activity by a Pseudouridine Synthase through Posttranscriptional Modification of Steroid Receptor RNA Activator

Molecular Cell ◽

10.1016/j.molcel.2004.06.044 ◽

2004 ◽

Vol 15 (4) ◽

pp. 549-558 ◽

Cited By ~ 84

Author(s):

Xiansi Zhao ◽

Jeffrey R. Patton ◽

Shannon L. Davis ◽

Brian Florence ◽

Sarah J. Ames ◽

...

Keyword(s):

Nuclear Receptor ◽

Steroid Receptor ◽

Receptor Activity ◽

Posttranscriptional Modification ◽

Pseudouridine Synthase

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BAG-1 diversely affects steroid receptor activity

Biochemical Journal ◽

10.1042/bj20111456 ◽

2011 ◽

Vol 441 (1) ◽

pp. 297-303 ◽

Cited By ~ 9

Author(s):

Regina T. Knapp ◽

Andrea Steiner ◽

Ulrike Schmidt ◽

Kathrin Hafner ◽

Florian Holsboer ◽

...

Keyword(s):

Androgen Receptor ◽

Heat Shock ◽

Heat Shock Protein 70 ◽

Mineralocorticoid Receptor ◽

Transcriptional Activity ◽

Steroid Receptors ◽

Steroid Receptor ◽

Receptor Activity ◽

High Homology ◽

Shed Light

Part of the cellular and physiological functions of BAG-1 (Bcl-2-associated athanogene 1) has been ascribed to the ability of this hsp70 (heat-shock protein 70) co-chaperone to regulate steroid receptor activity. BAG-1 has been reported to inhibit the GR (glucocorticoid receptor) and stimulate the androgen receptor, but to leave the activity of the MR (mineralocorticoid receptor) unchanged. Given the high homology between the MR and GR, this disparity in the actions of BAG-1 is surprising. In the present study, we analysed the effect of BAG-1 on the activity of the closely related PR (progesterone receptor). Similarly to the GR, the transcriptional activity of the PR is inhibited by the long and middle isoforms of BAG-1, BAG-1L and BAG-1M, but not by the short isoform, BAG-1S. We found this inhibition to require the hsp70-binding domain of BAG-1. To shed light on the mechanisms that could explain BAG-1's differential actions on steroid receptors, we tested the binding of BAG-1M to the PR. Mutational analyses of the PR and BAG-1M revealed that the mode of interaction and BAG-1M-mediated inhibition of the PR differs from the reported scenario for the GR. Surprisingly, we also found binding of BAG-1M to the MR. In addition, BAG-1M was able to inhibit the transcriptional activity of the MR. These data entail a reappraisal of the physiological actions of BAG-1M on steroid receptor activity.

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Steroid receptor coactivators 1, 2, and 3: Critical regulators of nuclear receptor activity and steroid receptor modulator (SRM)-based cancer therapy

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2011.04.021 ◽

2012 ◽

Vol 348 (2) ◽

pp. 430-439 ◽

Cited By ~ 88

Author(s):

Amber B. Johnson ◽

Bert W. O’Malley

Keyword(s):

Cancer Therapy ◽

Nuclear Receptor ◽

Steroid Receptor ◽

Receptor Activity ◽

Receptor Modulator ◽

Steroid Receptor Coactivators

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Development of potent small-molecule inhibitors to drug the undruggable steroid receptor coactivator-3

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1604274113 ◽

2016 ◽

Vol 113 (18) ◽

pp. 4970-4975 ◽

Cited By ~ 34

Author(s):

Xianzhou Song ◽

Jianwei Chen ◽

Mingkun Zhao ◽

Chengwei Zhang ◽

Yang Yu ◽

...

Keyword(s):

Breast Cancer ◽

Small Molecule ◽

Protein Interactions ◽

High Throughput Screening ◽

Small Molecule Inhibitors ◽

Structural Information ◽

Steroid Receptor ◽

Functional Assay ◽

Lipinski’S Rule ◽

Steroid Receptor Coactivator

Protein–protein interactions (PPIs) play a central role in most biological processes, and therefore represent an important class of targets for therapeutic development. However, disrupting PPIs using small-molecule inhibitors (SMIs) is challenging and often deemed as “undruggable.” We developed a cell-based functional assay for high-throughput screening to identify SMIs for steroid receptor coactivator-3 (SRC-3 or AIB1), a large and mostly unstructured nuclear protein. Without any SRC-3 structural information, we identified SI-2 as a highly promising SMI for SRC-3. SI-2 meets all of the criteria of Lipinski’s rule [Lipinski et al. (2001) Adv Drug Deliv Rev 46(1-3):3–26] for a drug-like molecule and has a half-life of 1 h in a pharmacokinetics study and a reasonable oral availability in mice. As a SRC-3 SMI, SI-2 can selectively reduce the transcriptional activities and the protein concentrations of SRC-3 in cells through direct physical interactions with SRC-3, and selectively induce breast cancer cell death with IC50 values in the low nanomolar range (3–20 nM), but not affect normal cell viability. Furthermore, SI-2 can significantly inhibit primary tumor growth and reduce SRC-3 protein levels in a breast cancer mouse model. In a toxicology study, SI-2 caused minimal acute cardiotoxicity based on a hERG channel blocking assay and an unappreciable chronic toxicity to major organs based on histological analyses. We believe that this work could significantly improve breast cancer treatment through the development of “first-in-class” drugs that target oncogenic coactivators.

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