Identification of Selective ERRγ Inverse Agonists

Kim, Jina; Im, Chun Young; Yoo, Eun Sang; Jung, Min-Jung; Kim, Sang-Bum; Hong, Eunmi; Chin, Jungwook; Hwang, Hayoung; Lee, Sung‐Woo; Kim, Nam Doo; Jeon, Jae‐Han; Lee, Inkyu; Jeon, Yong Hyun; Choi, Hueng‐Sik; Kim, Seong Heon; Cho, Sung Jin

doi:10.3390/molecules21010080

Cited by 15 publications

(14 citation statements)

References 20 publications

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“…A greater example would be the blockade of ERRγ (estrogen related receptor γ), an orphan nuclear receptor [ 58 , 59 ], which modulates fibrinogen levels in hypofibrinogenemia states caused by diet-induced obesity, diabetes mellitus type 2, liver injury and alcohol-induced oxidative stress [ 60 , 61 ]. Specifically, inverse agonists, such as GSK5182 (CAS: 877387-37-6) [ 60 , 61 , 62 , 63 , 64 , 65 , 66 ] and DN200434 [ 67 , 68 ], would offer such beneficial action through the decrease of fibrinogen levels.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Proteomic Study Unmasks Fibrinogen Pathway in Polycystic Liver Disease

et al. 2022

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(1) Background: Polycystic liver disease (PLD) is a heterogeneous group of congenital disorders characterized by bile duct dilatation and cyst development derived from cholangiocytes. Nevertheless, the cystogenesis mechanism is currently unknown and the PLD treatment is limited to liver transplantation. Novel and efficient therapeutic approaches are th6us needed. In this context, the present work has a principal aim to find novel molecular pathways, as well as new therapeutic targets, involved in the hepatic cystogenesis process. (2) Methods: Quantitative proteomics based on SWATH–MS technology were performed comparing hepatic proteomes of Wild Type and mutant/polycystic livers in a polycystic kidney disease (PKD) murine model (Pkd1cond/cond;Tam-Cre−/+). (3) Results: We identified several proteins altered in abundance, with two-fold cut-off up-regulation or down-regulation and an adjusted p-value significantly related to hepatic cystogenesis. Then, we performed enrichment and a protein–protein analysis identifying a cluster focused on hepatic fibrinogens. Finally, we validated a selection of targets by RT-qPCR, Western blotting and immunohistochemistry, finding a high correlation with quantitative proteomics data and validating the fibrinogen complex. (4) Conclusions: This work identified a novel molecular pathway in cystic liver disease, highlighting the fibrinogen complex as a possible new therapeutic target for PLD.

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Section: Discussionmentioning

confidence: 99%

Quantitative Proteomic Study Unmasks Fibrinogen Pathway in Polycystic Liver Disease

et al. 2022

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“…EC 50 values. They are chemically quite distinct from the tamoxifen derivatives recently reported by Korean researchers[26]. Claims are for obesity, diabetes, muscular dystrophy, nonalcoholic fatty liver disease and neurological disorders.Published: 21 February 2019 MeSH Keywords: diabetes mellitus / ESRRG protein, human…”

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confidence: 83%

Patent Highlights February–March 2019

Mucke¹

2019

Pharm. Pat. Anal.

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Use of substance directly or indirectly regulating YB-1 phosphorylation in preparation of drug for treating disease caused by inflammatory factors Inventors: Liu B Assignee: Jilin Zhong Tai Biotechnological Co. Ltd, Changchun (Jilin, China) Y-box binding proteins are multifunctional nucleic acid-binding proteins with an evolutionary conserved cold shock domain. Their dysregulated expression can influence transcription and translation on many levels and has been linked to cancer and inflammatory diseases [1]. The best investigated Y-box binding protein, YB-1 (also known as YBX1), locates to cytoplasmic P granules and stress granules, and is considered a target for drug-resistant cancer therapy [2]. The signaling pathways involved in stress-induced YB-1 phosphorylation have recently been described [3]. It is well known that YB-1 is an early and central mediator of noncancer inflammation, especially in the context of renal conditions [4,5]. The inventor claims MK-2206 (an allosteric Akt inhibitor for which the US National Cancer Institute had completed a Phase II clinical study in 2017) and dexamethasone as agents that control YB-1 phosphorylation (and hence, inflammation of almost any type) either directly or indirectly (through phosphorylation of YB-1 inhibitors). Data from experiments with fresh human arterial tissue and murine arteriosclerosis models are presented.

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“…We recently reported that the selective ERRg inverse agonist GSK5182 enhances NIS-mediated radioiodine uptake in ATC cells with either KRAS or BRAF mutations, promoting enhanced radioiodine therapy responsiveness in vitro (9). Toward discovering novel ERRg inverse agonists, we also reported several lead optimization studies including 4-hydroxytamoxifen analogue synthesis and biological evaluation (10,11). This finding provided a rationale for exploring new ERRg inverse agonists that effectively enhance NIS function in vivo and show potential for clinical translation to patients with ATC.…”

Section: Introductionmentioning

confidence: 95%

A Novel Orally Active Inverse Agonist of Estrogen-related Receptor Gamma (ERRγ), DN200434, A Booster of NIS in Anaplastic Thyroid Cancer

Singh

Song

Kim

et al. 2019

Clinical Cancer Research

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Purpose: New strategies to restore sodium iodide symporter (NIS) expression and function in radioiodine therapy-refractive anaplastic thyroid cancers (ATCs) are urgently required. Recently, we reported the regulatory role of estrogen-related receptor gamma (ERRg) in ATC cell NIS function. Herein, we identified DN200434 as a highly potent (functional IC 50 ¼ 0.006 mmol/L), selective, and orally available ERRg inverse agonist for NIS enhancement in ATC. Experimental Design: We sought to identify better ERRgtargeting ligands and explored the crystal structure of ERRg in complex with DN200434. After treating ATC cells with DN200434, the change in iodide-handling gene expression, as well as radioiodine avidity was examined. ATC tumorbearing mice were orally administered with DN200434, followed by 124 I-positron emission tomography/CT (PET/CT). For radioiodine therapy, ATC tumor-bearing mice treated with DN200434 were administered 131 I (beta ray-emitting therapeutic radioiodine) and then bioluminescent imaging was performed to monitor the therapeutic effects. Histologic analysis was performed to evaluate ERRg expression status in normal tissue and ATC tissue, respectively. Results: DN200434-ERRg complex crystallographic studies revealed that DN200434 binds to key ERRg binding pocket residues through four-way interactions. DN200434 effectively upregulated iodide-handling genes and restored radioiodine avidity in ATC tumor lesions, as confirmed by 124 I-PET/CT. DN200434 enhanced ATC tumor radioiodine therapy susceptibility, markedly inhibiting tumor growth. Histologic findings of patients with ATC showed higher ERRg expression in tumors than in normal tissue, supporting ERRg as a therapeutic target for ATC. Conclusions: DN200434 shows potential clinical applicability for diagnosis and treatment of ATC or other poorly differentiated thyroid cancers.

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Identification of Selective ERRγ Inverse Agonists

Cited by 15 publications

References 20 publications

Quantitative Proteomic Study Unmasks Fibrinogen Pathway in Polycystic Liver Disease

Quantitative Proteomic Study Unmasks Fibrinogen Pathway in Polycystic Liver Disease

Patent Highlights February–March 2019

A Novel Orally Active Inverse Agonist of Estrogen-related Receptor Gamma (ERRγ), DN200434, A Booster of NIS in Anaplastic Thyroid Cancer

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