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

24 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)

Access to Document

10.1021/cc900081j

Fingerprint Dive into the research topics of 'Efficient discovery of selective small molecule agonists of estrogen-related receptor γ using combinatorial approach'. Together they form a unique fingerprint.

Cite this

@article{f8e7ad6e7b434c7d98b60e80d290a40f,

title = "Efficient discovery of selective small molecule agonists of estrogen-related receptor γ using combinatorial approach",

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.",

author = "Yongju Kim and Minseob Koh and Kim, {Don Kyu} and Choi, {Hueng Sik} and Park, {Seung Bum}",

year = "2009",

month = sep,

day = "14",

doi = "10.1021/cc900081j",

language = "English",

volume = "11",

pages = "928--937",

journal = "ACS Combinatorial Science",

issn = "2156-8952",

publisher = "American Chemical Society",

number = "5",

}

TY - JOUR

T1 - Efficient discovery of selective small molecule agonists of estrogen-related receptor γ using combinatorial approach

AU - Kim, Yongju

AU - Koh, Minseob

AU - Kim, Don Kyu

AU - Choi, Hueng Sik

AU - Park, Seung Bum

PY - 2009/9/14

Y1 - 2009/9/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=70349330695&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349330695&partnerID=8YFLogxK

U2 - 10.1021/cc900081j

DO - 10.1021/cc900081j

M3 - Article

C2 - 19746993

AN - SCOPUS:70349330695

VL - 11

SP - 928

EP - 937

JO - ACS Combinatorial Science

JF - ACS Combinatorial Science

SN - 2156-8952

IS - 5

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Cite this