Discovery of a New Class of Liver Receptor Homolog‐1 (LRH‐1) Antagonists: Virtual Screening, Synthesis and Biological Evaluation

Rey, Jullien; Hu, Haipeng; Kyle, Fiona; Lai, Chun‐Fui; Buluwela, Laki; Coombes, R. Charles; Ortlund, Eric A.; Ali, Simak; Snyder, James P.; Barrett, Anthony G. M.

doi:10.1002/cmdc.201200307

Cited by 27 publications

(24 citation statements)

References 47 publications

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“…Additionally, treatment of cells transgenic for human Lrh-1 with RJW100 results in the ability to resolve high levels of ER stress and protection from cell death following stress. Therefore, targeting LRH-1 in vivo with agonists or newly developed antagonists (Rey et al, 2012) may allow selective augmentation or inhibition of ER stress resolution, which could prove beneficial in numerous human disorders. This is of particular interest since other strategies for targeting the UPR have proven to be difficult, and no chemical compounds have been successfully used in mice that directly activate downstream UPR components.…”

Section: Discussionmentioning

confidence: 99%

Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution

Mamrosh

Lee

Wagner

et al. 2014

eLife

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Chronic endoplasmic reticulum (ER) stress results in toxicity that contributes to multiple human disorders. We report a stress resolution pathway initiated by the nuclear receptor LRH-1 that is independent of known unfolded protein response (UPR) pathways. Like mice lacking primary UPR components, hepatic Lrh-1-null mice cannot resolve ER stress, despite a functional UPR. In response to ER stress, LRH-1 induces expression of the kinase Plk3, which phosphorylates and activates the transcription factor ATF2. Plk3-null mice also cannot resolve ER stress, and restoring Plk3 expression in Lrh-1-null cells rescues ER stress resolution. Reduced or heightened ATF2 activity also sensitizes or desensitizes cells to ER stress, respectively. LRH-1 agonist treatment increases ER stress resistance and decreases cell death. We conclude that LRH-1 initiates a novel pathway of ER stress resolution that is independent of the UPR, yet equivalently required. Targeting LRH-1 may be beneficial in human disorders associated with chronic ER stress.DOI: http://dx.doi.org/10.7554/eLife.01694.001

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Section: Discussionmentioning

confidence: 99%

Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution

Mamrosh

Lee

Wagner

et al. 2014

eLife

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“…Recent reports provide evidence regarding compounds with such activities [36][37][38][39], which should be explored in future studies.…”

Section: Discussionmentioning

confidence: 97%

Nuclear receptor NR5A2 is involved in the calreticulin gene regulation during renal fibrosis

Arvaniti

Vakrakou

Kaltezioti

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…These compounds induced the activation of the small ubiquitin-like modifier-dependent transrepression function of LRH-1 and subsequent inhibition of induction of proinflammatory genes in the liver acute-phase response (Venteclef et al, 2010). More recently, synthetic repressors of LRH-1 activity have been reported (Busby et al, 2010;Rey et al, 2012;Benod et al, 2013). Here we report the characterization of SR1848 [ML180; CID 3238389; 6-[4-(3-chlorophenyl)piperazin-1-yl]-3-cyclohexyl-1H-pyrimidine-2,4-dione] (Fig.…”

Section: Introductionmentioning

confidence: 99%

Antiproliferation Activity of a Small Molecule Repressor of Liver Receptor Homolog 1

et al. 2014

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The orphan nuclear receptor liver receptor homolog 1 (LRH-1; NR5A2) is a potent regulator of cholesterol metabolism and bile acid homeostasis. Recently, LRH-1 has been shown to play an important role in intestinal inflammation and in the progression of estrogen receptor positive and negative breast cancers and pancreatic cancer. Structural studies have revealed that LRH-1 can bind phospholipids and the dietary phospholipid dilauroylphosphatidylcholine activates LRH-1 activity in rodents. Here we characterize the activity of a novel synthetic nonphospholipid small molecule repressor of LRH-1, SR1848 (6-[4-(3-chlorophenyl) piperazin-1-yl]-3-cyclohexyl-1H-pyrimidine-2,4-dione). In cotransfection studies, SR1848 reduced LRH-1-dependent expression of a reporter gene and in cells that endogenously express LRH-1 dose dependently reduced the expression of cyclin-D1 and -E1, resulting in inhibition of cell proliferation. The cellular effects of SR1848 treatment are recapitulated after transfection of cells with small-interfering RNA targeting LRH-1. Immunocytochemistry analysis shows that SR1848 induces rapid translocation of nuclear LRH-1 to the cytoplasm. Combined, these results suggest that SR1848 is a functional repressor of LRH-1 that impacts expression of genes involved in proliferation in LRH-1-expressing cancers. Thus, SR1848 represents a novel chemical scaffold for the development of therapies targeting malignancies driven by LRH-1.

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Discovery of a New Class of Liver Receptor Homolog‐1 (LRH‐1) Antagonists: Virtual Screening, Synthesis and Biological Evaluation

Cited by 27 publications

References 47 publications

Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution

Nuclear receptor LRH-1/NR5A2 is required and targetable for liver endoplasmic reticulum stress resolution

Nuclear receptor NR5A2 is involved in the calreticulin gene regulation during renal fibrosis

Antiproliferation Activity of a Small Molecule Repressor of Liver Receptor Homolog 1

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