ERRα agonists(estrogen related receptor alpha agonists)、ERRβ agonists(estrogen related receptor beta agonists)、ESRRG agonists(estrogen related receptor gamma agonists)

治疗领域

内分泌与代谢疾病

在研适应症

代谢综合征代谢性疾病

非在研适应症-

原研机构

Washington University School of Medicine

在研机构

Washington University School of Medicine

St. Louis College of Pharmacy

非在研机构-

最高研发阶段临床前

首次获批日期-

最高研发阶段(中国)-

特殊审评-

关联

100 项与 SLU-PP-332 相关的临床结果

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100 项与 SLU-PP-332 相关的转化医学

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100 项与 SLU-PP-332 相关的专利（医药）

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项与 SLU-PP-332 相关的文献（医药）

2024-02-01·The Journal of Pharmacology and Experimental Therapeutics

A Synthetic ERR Agonist Alleviates Metabolic Syndrome

Article

作者: Chatterjee, Arindam ; Avdagic, Amer ; Burris, Thomas P ; Billon, Cyrielle ; Elgendy, Bahaa ; Butler, Andrew A ; Walker, John K ; Schoepke, Emmalie

Physical exercise induces physiologic adaptations and is effective at reducing the risk of premature death from all causes. Pharmacological exercise mimetics may be effective in the treatment of a range of diseases including obesity and metabolic syndrome. Previously, we described the development of SLU-PP-332, an agonist for the estrogen-related receptor (ERR)α, β, and γ nuclear receptors that activates an acute aerobic exercise program. Here we examine the effects of this exercise mimetic in mouse models of obesity and metabolic syndrome. Diet-induced obese or ob/ob mice were administered SLU-PP-332, and the effects on a range of metabolic parameters were assessed. SLU-PP-332 administration mimics exercise-induced benefits on whole-body metabolism in mice including increased energy expenditure and fatty acid oxidation. These effects were accompanied by decreased fat mass accumulation. Additionally, the ERR agonist effectively reduced obesity and improved insulin sensitivity in models of metabolic syndrome. Pharmacological activation of ERR may be an effective method to treat metabolic syndrome and obesity. SIGNIFICANCE STATEMENT: An estrogen receptor-related orphan receptor agonist, SLU-PP-332, with exercise mimetic activity, holds promise as a therapeutic to treat metabolic diseases by decreasing fat mass in mouse models of obesity.

2024-01-16·Circulation

Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function

Article

作者: Qi, Lei ; Hong, Seok Jae ; Zhang, Lilei ; Jensen, Brian C. ; Wilderman, Andrea ; Rideb, Jernie Rae Dela Cruz ; Hayes, Matthew ; Downes, Michael ; Hampton, Carissa S. ; Adeyemi, Christiana M. ; Evans, Ronald M. ; Graves, Andrea ; Fu, Chen ; Fan, Weiwei ; Nasiotis, Eleni ; Welch, Ryan D. ; Xu, Weiyi ; Yu, Keyang ; Losby, McKenna ; Li, Hui ; Walker, John K. ; Zhao, Yuanbiao ; Pei, Liming ; Milosavljevic, Aleksandar ; Billon, Cyrielle ; Oh, Tae Gyu ; Burris, Thomas

BACKGROUND:Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF. However, in vivo studies demonstrating the potential usefulness of ERR agonist for HF treatment are lacking, because compounds with pharmacokinetics appropriate for in vivo use have not been available.METHODS:Using a structure-based design approach, we designed and synthesized 2 structurally distinct pan-ERR agonists, SLU-PP-332 and SLU-PP-915. We investigated the effect of ERR agonist on cardiac function in a pressure overload–induced HF model in vivo. We conducted comprehensive functional, multi-omics (RNA sequencing and metabolomics studies), and genetic dependency studies both in vivo and in vitro to dissect the molecular mechanism, ERR isoform dependency, and target specificity.RESULTS:Both SLU-PP-332 and SLU-PP-915 significantly improved ejection fraction, ameliorated fibrosis, and increased survival associated with pressure overload–induced HF without affecting cardiac hypertrophy. A broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function. Metabolomics analysis showed substantial normalization of metabolic profiles in fatty acid/lipid and tricarboxylic acid/oxidative phosphorylation metabolites in the mouse heart with 6-week pressure overload. ERR agonists increase mitochondria oxidative capacity and fatty acid use in vitro and in vivo. Using both in vitro and in vivo genetic dependency experiments, we show that ERRγ is the main mediator of ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocytes.CONCLUSIONS:ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload–induced HF in vivo. Our results provide direct pharmacologic evidence supporting the further development of ERR agonists as novel HF therapeutics.

2023-12-01·The American Journal of Pathology

Estrogen-Related Receptor Agonism Reverses Mitochondrial Dysfunction and Inflammation in the Aging Kidney

Article

作者: Elgendy, Bahaa ; Jones, Bryce A ; Myakala, Komuraiah ; Chatterjee, Arindam ; Takahashi, Shogo ; Libby, Andrew E ; Bhasin, Kanchan ; Burris, Thomas P ; Walker, John K ; Albanese, Chris ; Titievsky, Avi ; Levi, Moshe ; Wang, Xiaoxin X ; Gonzalez, Frank J ; Taranenko, Elizaveta ; Zerfas, Patricia M ; Krausz, Kristopher W ; Panov, Julia ; Daneshpajouhnejad, Parnaz ; Kopp, Jeffrey B ; Brodsky, Leonid ; Guha, Udayan ; Rosenberg, Avi Z ; Qi, Yue ; Krawczyk, Ewa ; Shults, Nataliia ; Billon, Cyrielle

A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging, per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. This study examined the role of the nuclear hormone receptors, the estrogen-related receptors (ERRs), in regulation of age-related mitochondrial dysfunction and inflammation. The ERRs were decreased in both aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR). A pan-ERR agonist, SLU-PP-332, was used to treat 21-month-old mice for 8 weeks. In addition, 21-month-old mice were treated with a stimulator of interferon genes (STING) inhibitor, C-176, for 3 weeks. Remarkably, similar to CR, an 8-week treatment with a pan-ERR agonist reversed the age-related increases in albuminuria, podocyte loss, mitochondrial dysfunction, and inflammatory cytokines, via the cyclic GMP-AMP synthase-STING and STAT3 signaling pathways. A 3-week treatment of 21-month-old mice with a STING inhibitor reversed the increases in inflammatory cytokines and the senescence marker, p21/cyclin dependent kinase inhibitor 1A (Cdkn1a), but also unexpectedly reversed the age-related decreases in PPARG coactivator (PGC)-1α, ERRα, mitochondrial complexes, and medium chain acyl coenzyme A dehydrogenase (MCAD) expression. These studies identified ERRs as CR mimetics and as important modulators of age-related mitochondrial dysfunction and inflammation. These findings highlight novel druggable pathways that can be further evaluated to prevent progression of age-related kidney disease.

100 项与 SLU-PP-332 相关的药物交易

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