Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRγ

Esther Y.H. Chao; Jon L. Collins; Stéphanie Gaillard; Aaron B. Miller; Liping Wang; Lisa A. Orband-Miller; Robert T. Nolte; Donald P. McDonnell; Timothy M. Willson; William J. Zuercher

doi:10.1016/j.bmcl.2005.11.030

Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRγ

Esther Y.H. Chao, Jon L. Collins, Stéphanie Gaillard, Aaron B. Miller, Liping Wang, Lisa A. Orband-Miller, Robert T. Nolte, Donald P. McDonnell, Timothy M. Willson, William J. Zuercher

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

Abstract

The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor γ and the classical estrogen receptor α demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERRγ LBD confirms the molecular basis of the selectivity.

Original language	English (US)
Pages (from-to)	821-824
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	16
Issue number	4
DOIs	https://doi.org/10.1016/j.bmcl.2005.11.030
State	Published - Feb 15 2006
Externally published	Yes

Keywords

ERRγ chemical tool
Orphan nuclear receptor

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2005.11.030

Cite this

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title = "Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRγ",

abstract = "The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor γ and the classical estrogen receptor α demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERRγ LBD confirms the molecular basis of the selectivity.",

keywords = "ERRγ chemical tool, Orphan nuclear receptor",

author = "Chao, {Esther Y.H.} and Collins, {Jon L.} and St{\'e}phanie Gaillard and Miller, {Aaron B.} and Liping Wang and Orband-Miller, {Lisa A.} and Nolte, {Robert T.} and McDonnell, {Donald P.} and Willson, {Timothy M.} and Zuercher, {William J.}",

note = "Funding Information: The authors thank Randy Bledsoe and Thomas Consler for protein expression and Anthony Handlon and Ryan Trump for helpful discussions and critical review. S.G. and D.P.M. acknowledge the support of the NIH (NURSA U19 DK062434).",

year = "2006",

month = feb,

day = "15",

doi = "10.1016/j.bmcl.2005.11.030",

language = "English (US)",

volume = "16",

pages = "821--824",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

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TY - JOUR

T1 - Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRγ

AU - Chao, Esther Y.H.

AU - Collins, Jon L.

AU - Gaillard, Stéphanie

AU - Miller, Aaron B.

AU - Wang, Liping

AU - Orband-Miller, Lisa A.

AU - Nolte, Robert T.

AU - McDonnell, Donald P.

AU - Willson, Timothy M.

AU - Zuercher, William J.

N1 - Funding Information: The authors thank Randy Bledsoe and Thomas Consler for protein expression and Anthony Handlon and Ryan Trump for helpful discussions and critical review. S.G. and D.P.M. acknowledge the support of the NIH (NURSA U19 DK062434).

PY - 2006/2/15

Y1 - 2006/2/15

N2 - The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor γ and the classical estrogen receptor α demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERRγ LBD confirms the molecular basis of the selectivity.

AB - The design and synthesis of 4-hydroxytamoxifen (4-OHT) derivatives are described. The binding affinities of these compounds toward the orphan estrogen-related receptor γ and the classical estrogen receptor α demonstrate that analogs bearing hydroxyalkyl groups display improved binding selectivity profiles compared with that of 4-OHT. An X-ray crystal structure of one of the designed compounds bound to ERRγ LBD confirms the molecular basis of the selectivity.

KW - ERRγ chemical tool

KW - Orphan nuclear receptor

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UR - http://www.scopus.com/inward/citedby.url?scp=30344481949&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2005.11.030

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M3 - Article

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VL - 16

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 4

ER -

Structure-guided synthesis of tamoxifen analogs with improved selectivity for the orphan ERRγ

Abstract

Keywords

ASJC Scopus subject areas

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