Synthesis and biological evaluation of novel 4-hydroxytamoxifen analogs as estrogen-related receptor gamma inverse agonists

Kim, Jina; Chin, Jungwook; Im, Chun Young; Yoo, Eun Sang; Woo, Seoyeon; Hwang, Hee-Jong; Cho, Joong-heui; Seo, Kyung-Ah; Song, Jae‐Young; Hwang, Hayoung; Kim, Kyung‐Hee; Kim, Nam Doo; Yoon, Sunkyung; Jeon, Jae‐Han; Yoon, Seungyun; Jeon, Yong Hyun; Choi, Hueng‐Sik; Lee, Inkyu; Kim, Seong Heon; Cho, Sung Jin

doi:10.1016/j.ejmech.2016.04.076

Cited by 17 publications

(12 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…33 Previously, our reports have shown that inverse agonists of ERRγ are able to restore the ability of radioiodine uptake in ATC cells by an increase of NIS protein that results from the downregulation of endogenous ERRγ protein and activation of MAP kinase. 31,30 Thus, we examined the effects of 6g and 10b on NIS, ERRγ, and phosphorylated ERK1/2 levels in ATC cells, CAL62 cells. 6g and 10b induced significant inhibition of endogenous ERRγ protein levels in CAL62 cells in a dose-dependent manner (Figure 2A,B and Figure 3A,B).…”

Section: Table 4 In Vitro Binding Selectivity Of the Screened 20 Comp...mentioning

confidence: 99%

“…28 On the basis of the structural motifs of 3, we have successfully demonstrated the synthesis of compound libraries that are more selective against ERRγ inverse agonists with improved absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles. 29,30 Moreover, we have broadened the therapeutic scope of these compounds based on our findings that 3 facilitates the responsiveness to radioiodine therapy by modulating sodium iodine symporter (NIS) function in anaplastic thyroid cancer (ATC) cells via ERRγ and MAP kinase signaling pathway. 31 On the basis of these encouraging results, we have validated the most promising compound of 3 analog from our previous studies for its ability to enhance NIS protein function, which is a key protein for radioiodine therapy, in ATC cells.…”

Section: ■ Introductionmentioning

confidence: 99%

“…31 On the basis of these encouraging results, we have validated the most promising compound of 3 analog from our previous studies for its ability to enhance NIS protein function, which is a key protein for radioiodine therapy, in ATC cells. 30 However, we remain attentive to the development of small ERRγ ligands with much more enhanced pharmacological and ADMET profiles.…”

Section: ■ Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Insights of a Lead Optimization Study and Biological Evaluation of Novel 4-Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists

Kim

Woo

et al. 2016

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

We evaluated the in vitro pharmacology as well as the absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of chemical entities that not only were shown to be highly selective agonists for ERRγ but also exhibited enhanced pharmacokinetic profile compared with 3 (GSK5182). 6g and 10b had comparable potency to 3 and were far more selective for ERRγ over the ERRα, -β, and ERα. The in vivo pharmacokinetic profiles of 6g and 10b were further evaluated, as they possessed superior in vitro ADMET profiles compared to the other compounds. Additionally, we observed a significant increase of fully glycosylated NIS protein, key protein for radioiodine therapy in anaplastic thyroid cancer (ATC), in 6g- or 10b-treated CAL62 cells, which indicated that these compounds could be promising enhancers for restoring NIS protein function in ATC cells. Thus, 6g and 10b possess advantageous druglike properties and can be used to potentially treat various ERRγ-related disorders.

show abstract

Section: Table 4 In Vitro Binding Selectivity Of the Screened 20 Comp...mentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Insights of a Lead Optimization Study and Biological Evaluation of Novel 4-Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists

Kim

Woo

et al. 2016

J. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Pam3CSK4 (TLR1/2 ligand; tri‐palmitoylated lipopeptide), poly(I:C) (TLR3 ligand), ultrapure LPS (TLR4 ligand) and R848 (TLR7/8 ligand) were purchased from Invivogen (San Diego, CA, USA); 614310 (TLR3/dsRNA complex inhibitor) was purchased from Merck Millipore (Billerica, MA, USA); and SP600125 (JNK inhibitor) and Bay11‐7082 (NF‐κB inhibitor) were purchased from Cell Signaling Technology (Danvers, MA, USA). GSK5182, an inverse agonist of ERRγ, was synthesized and dissolved for in vitro and in vivo experiments as previously described 29,34–36 . All reagents were dissolved in the recommended solvents.…”

Section: Methodsmentioning

confidence: 99%

“…GSK5182, an inverse agonist of ERR , was synthesized and dissolved for in vitro and in vivo experiments as previously described. 29,[34][35][36] All reagents were dissolved in the recommended solvents.…”

Section: Reagentsmentioning

confidence: 99%

Frontline Science: Estrogen-related receptor γ increases poly(I:C)-mediated type I IFN expression in mouse macrophages

Kim

et al. 2020

Journal of Leukocyte Biology

Self Cite

View full text Add to dashboard Cite

Although type I IFNs (IFN-I) are important for the innate and adaptive immune responses to suppress viral replication, prolonged IFN-I signaling in macrophages suppresses the immune response. Nuclear receptor estrogen-related receptor (ERR ) regulates the transcription of genes involved in endocrine and metabolic functions. However, the role of ERR in macrophage immune responses to viruses remains largely unknown. ERR expression was significantly induced in mouse bone marrow-derived macrophages (BMDMs) treated with polyinosinic-polycytidylic acid (poly(I:C)). Our results indicated that the induction of ERR expression by poly(I:C) is mediated through activation of the cytoplasmic dsRNA receptors, retinoic acid-inducible gene I and melanoma differentiation-associated protein 5. In BMDMs, overexpression of ERR significantly increased gene expression and secretion of the IFN-I genes, IFN-and IFN-, whereas abolition of ERR significantly attenuated poly(I:C)-mediated IFN-I secretion. Chromatin immunoprecipitation assays and mutation analyses of the IFN-I promoters revealed that ERR regulates the transcription of IFN-and IFN-by binding to a conserved ERR response element in each promoter region. Finally, GSK5182 significantly suppressed poly(I:C)-mediated induction of IFN-I gene expression and secretion in BMDMs. Taken together, these findings reveal a previously unrecognized role for ERR in the transcriptional control of innate and adaptive immune response to dsRNA virus replication.

show abstract

In Silico Prediction of ERRα Agonists Based on Combined Features and Stacking Ensemble Method

Xu,

Huang,

Duan

et al. 2024

ChemMedChem

View full text Add to dashboard Cite

Estrogen‐related receptor α (ERRα) is considered a very promising target for treating metabolic diseases such as type 2 diabetes. Development of a prediction model to quickly identify potential ERRα agonists can significantly reduce the time spent on virtual screening. In this study, 298 ERRα agonists and numerous nonagonists were collected from various sources to build a new dataset of ERRα agonists. Then a total of 90 models were built using a combination of different algorithms, molecular characterization methods, and data sampling techniques. The consensus model with optimal performance was also validated on the test set (AUC=0.876, BA=0.816) and external validation set (AUC=0.867, BA=0.777) based on five selected baseline models. Furthermore, the model's applicability domain and privileged substructures were examined, and the feature importance was analyzed using the SHAP method to help interpret the model. Based on the above, it’s hoped that our publicly accessible data, models, codes, and analytical techniques will prove valuable in quick screening and rational designing more novel and potent ERRα agonists.

show abstract

Synthesis and biological evaluation of novel 4-hydroxytamoxifen analogs as estrogen-related receptor gamma inverse agonists

Cited by 17 publications

References 27 publications

Insights of a Lead Optimization Study and Biological Evaluation of Novel 4-Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists

Insights of a Lead Optimization Study and Biological Evaluation of Novel 4-Hydroxytamoxifen Analogs as Estrogen-Related Receptor γ (ERRγ) Inverse Agonists

Frontline Science: Estrogen-related receptor γ increases poly(I:C)-mediated type I IFN expression in mouse macrophages

In Silico Prediction of ERRα Agonists Based on Combined Features and Stacking Ensemble Method

Contact Info

Product

Resources

About