Efficient discovery of selective small molecule agonists of estrogen-related receptor γ using combinatorial approach

Yongju Kim; Minseob Koh; Don Kyu Kim; Hueng Sik Choi; Seung Bum Park

doi:10.1021/cc900081j

Efficient discovery of selective small molecule agonists of estrogen-related receptor γ using combinatorial approach

Yongju Kim, Minseob Koh, Don Kyu Kim, Hueng Sik Choi, Seung Bum Park

Research output: Contribution to journal › Article › peer-review

22 Citations (Scopus)

Abstract

With the goal of discovering a selective agonist of estrogen-related receptor γ (ERRγ) with enhanced potency, we designed a series of small-molecule ligands derived from a known ERRγ agonist, GSK4716, that can substantially potentiate the transcriptional activity of ERRγ. Individual compounds among a 30-member library of acyl hydrazones were pre-evaluated through in silico docking studies on the receptor cavities of ERRγ LBDs using X-ray crystal structures cocrystallized with GSK4716 and 4-OHT. This rational approach to achieve the enhanced potency in ERRγ transcriptional activity with selectivity over ERRα/βenables us to complete the construction of a focused library by carrying out microwave-assisted parallel synthesis with excellent yields and purities. Finally, we identified a more potent ERRγ agonist, E6, with excellent selectivity over ERRα/β.

Original language	English
Pages (from-to)	928-937
Number of pages	10
Journal	Journal of Combinatorial Chemistry
Volume	11
Issue number	5
DOIs	https://doi.org/10.1021/cc900081j
Publication status	Published - 2009 Sep 14
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)

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10.1021/cc900081j

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abstract = "With the goal of discovering a selective agonist of estrogen-related receptor γ (ERRγ) with enhanced potency, we designed a series of small-molecule ligands derived from a known ERRγ agonist, GSK4716, that can substantially potentiate the transcriptional activity of ERRγ. Individual compounds among a 30-member library of acyl hydrazones were pre-evaluated through in silico docking studies on the receptor cavities of ERRγ LBDs using X-ray crystal structures cocrystallized with GSK4716 and 4-OHT. This rational approach to achieve the enhanced potency in ERRγ transcriptional activity with selectivity over ERRα/βenables us to complete the construction of a focused library by carrying out microwave-assisted parallel synthesis with excellent yields and purities. Finally, we identified a more potent ERRγ agonist, E6, with excellent selectivity over ERRα/β.",

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AU - Kim, Yongju

AU - Koh, Minseob

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AU - Choi, Hueng Sik

AU - Park, Seung Bum

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