Identification of Diaryl Ether-Based Ligands for Estrogen-Related Receptor α as Potential Antidiabetic Agents

Patch, Raymond J.; Searle, Lily L.; Kim, Alexander J.; De, Debyendu; Zhu, Xizhen; Askari, Hossein B.; O’Neill, John C.; Abad, Marta C.; Rentzeperis, Dionisios; Liu, Jianying; Kemmerer, Michael; Lin, Ling; Kasturi, Jyotsna; Geisler, John G.; Lenhard, James M.; Player, Mark R.; Gaul, Micheal D.

doi:10.1021/jm101063h

Cited by 141Estrogen and related hormone effectsPeroxisome Proliferator-Activated ReceptorsSynthesis and biological activity

Identification of Diaryl Ether-Based Ligands for Estrogen-Related Receptor α as Potential Antidiabetic Agents

Patch, Raymond J., Searle, Lily L., Kim, Alexander J., De, Debyendu, Zhu, Xizhen, Askari, Hossein B., O’Neill, John C., Abad, Marta C. +9 more·2011·Journal of Medicinal Chemistry

DOI 10.1021/jm101063h

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Abstract

Estrogen-related receptor α (ERRα) is an orphan nuclear receptor that has been functionally implicated in the regulation of energy homeostasis. Herein is described the development of diaryl ether based thiazolidenediones, which function as selective ligands against this receptor. Series optimization provided several potent analogues that inhibit the recruitment of a coactivator peptide fragment in in vitro biochemical assays (IC(50) < 150 nM) and cellular two-hybrid reporter assays against the ligand binding domain (IC(50) = 1-5 μM). A cocrystal structure of the ligand-binding domain of ERRα with lead compound 29 revealed the presence of a covalent interaction between the protein and ligand, which has been shown to be reversible. In diet-induced murine models of obesity and in an overt diabetic rat model, oral administration of 29 normalized insulin and circulating triglyceride levels, improved insulin sensitivity, and was body weight neutral. This provides the first demonstration of functional activities of an ERRα ligand in metabolic animal models.

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VHL PROTACs targeting ERRα or RIPK2 achieved efficient degradation of both proteins at doses ranging from 3 nM (RIPK2) to 100 nM (ERRα).
“Using a warhead targeting either the estrogen-related receptor alpha (ERRα) [91] or the serine threonine kinase RIPK2, efficient degradation of both proteins could be achieved with doses ranging from 3 nM (RIPK2) to 100 nM (ERRα) [20].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [91]

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Authors: Patch, R. J., Searle, L. L., Kim, A. J., De, D., Zhu, X., Askari, H. B., O’Neill, J. C., Abad, M. C., Rentzeperis, D., Liu, J., Kemmerer, M., Lin, L., Kasturi, J., Geisler, J. G., Lenhard, J. M., Player, M. R., & Gaul, M. D.
Affiliations: Janssen Research & Development (United States) (US)
Corresponding author: Player, Mark R.
ORCID: Patch, Raymond J.
Kim, Alexander J.
Player, Mark R.
Venue: Journal of Medicinal Chemistry
Publisher: American Chemical Society (ACS)
Published: 2011-01-10
Volume: 54
Issue: 3
Pages: 788-808
ISSN: 0022-2623 (ISSN-L)
1520-4804
DOI: 10.1021/jm101063h
OpenAlex: W2329768612
Cited by: 141
References: 58
Citations by year: 2026: 2 · 2025: 9 · 2024: 13 · 2023: 17 · 2022: 11 · 2021: 13 · 2020: 13 · 2019: 10 · 2018: 6 · 2017: 6 · 2016: 9 · 2015: 8 · 2014: 4 · 2013: 9 · 2012: 8
FWCI: 4.99
Type: journal article
Language: en
Open access: closed
Locations: Journal of Medicinal Chemistry (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
Keywords: estrogen-related receptor alpha, nuclear receptor ligands, antidiabetic drugs, diet-induced obesity, insulin sensitivity, triglyceride levels, energy homeostasis, oral antidiabetic drugs
MeSH terms: ERRalpha Estrogen-Related Receptor, Administration, Oral, Animals, Binding, Competitive, Biological Availability, Diabetes Mellitus, Dogs, Ethers, Female, Humans, Hypoglycemic Agents, Insulin, Insulin Resistance, Ligands, Macaca fascicularis, Male, Models, Molecular, Obesity, Receptors, Estrogen, Structure-Activity Relationship, Triglycerides, Molecular Structure, Rats, Sprague-Dawley, Mice, Knockout, Crystallography, X-Ray, Thiazolidinediones, Mice, Rats

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Identification of Diaryl Ether-Based Ligands for Estrogen-Related Receptor α as Potential Antidiabetic Agents

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