Discovery of a Novel Class of ERRα Agonists

A novel class of estrogen-related receptor α (ERRα) agonists has been discovered. A structure–activity relationship study of high-throughput screening hits 1 and 2 led to the discovery of benzimidazole 3d (DS20362725) and acetophenone analogue 5c (DS45500853). The X-ray crystal structure of the ERRα...

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Published inACS medicinal chemistry letters Vol. 12; no. 5; pp. 817 - 821
Main Authors Shinozuka, Tsuyoshi, Ito, Shuichiro, Kimura, Takako, Izumi, Masanori, Wakabayashi, Kenji
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 13.05.2021
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Letter
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
crystal structure
ERRα
PPARγ
TZD
COMPLEX
CRYSTAL-STRUCTURE
PROLIFERATOR-ACTIVATED RECEPTOR
IDENTIFICATION
PPAR gamma
METABOLISM
ERR alpha
INVERSE AGONIST
LIGAND-BINDING DOMAIN
EXPRESSION
REVEALS
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Summary:A novel class of estrogen-related receptor α (ERRα) agonists has been discovered. A structure–activity relationship study of high-throughput screening hits 1 and 2 led to the discovery of benzimidazole 3d (DS20362725) and acetophenone analogue 5c (DS45500853). The X-ray crystal structure of the ERRα ligand-binding domain in complex with 5c and PGC-1α coactivator peptide revealed conformational changes in the ligand-binding pocket to accommodate 5c and the key interaction between the protein and ligand. Since both analogues avoided PPARγ transcriptional activity, they can be useful tool compounds for investigating biological ERRα functions.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.1c00100