Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators

Haley Hieronymus; Justin Lamb; Kenneth N. Ross; Xiao P. Peng; Cristina Clement; Anna Rodina; Maria Nieto; Jinyan Du; Kimberly Stegmaier; Srilakshmi M. Raj; Katherine N. Maloney; Jon Clardy; William C. Hahn; Gabriela Chiosis; Todd R. Golub

doi:10.1016/j.ccr.2006.09.005

Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators

Haley Hieronymus, Justin Lamb, Kenneth N. Ross, Xiao P. Peng, Cristina Clement, Anna Rodina, Maria Nieto, Jinyan Du, Kimberly Stegmaier, Srilakshmi M. Raj, Katherine N. Maloney, Jon Clardy, William C. Hahn, Gabriela Chiosis, Todd R. Golub

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

489 Scopus citations

Abstract

Although androgen receptor (AR)-mediated signaling is central to prostate cancer, the ability to modulate AR signaling states is limited. Here we establish a chemical genomic approach for discovery and target prediction of modulators of cancer phenotypes, as exemplified by AR signaling. We first identify AR activation inhibitors, including a group of structurally related compounds comprising celastrol, gedunin, and derivatives. To develop an in silico approach for target pathway identification, we apply a gene expression-based analysis that classifies HSP90 inhibitors as having similar activity to celastrol and gedunin. Validating this prediction, we demonstrate that celastrol and gedunin inhibit HSP90 activity and HSP90 clients, including AR. Broadly, this work identifies new modes of HSP90 modulation through a gene expression-based strategy.

Original language	English (US)
Pages (from-to)	321-330
Number of pages	10
Journal	Cancer Cell
Volume	10
Issue number	4
DOIs	https://doi.org/10.1016/j.ccr.2006.09.005
State	Published - Oct 2006
Externally published	Yes

Keywords

CELLCYCLE
CHEMBIO

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccr.2006.09.005

Cite this

Hieronymus, H., Lamb, J., Ross, K. N., Peng, X. P., Clement, C., Rodina, A., Nieto, M., Du, J., Stegmaier, K., Raj, S. M., Maloney, K. N., Clardy, J., Hahn, W. C., Chiosis, G., & Golub, T. R. (2006). Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators. Cancer Cell, 10(4), 321-330. https://doi.org/10.1016/j.ccr.2006.09.005

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title = "Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators",

abstract = "Although androgen receptor (AR)-mediated signaling is central to prostate cancer, the ability to modulate AR signaling states is limited. Here we establish a chemical genomic approach for discovery and target prediction of modulators of cancer phenotypes, as exemplified by AR signaling. We first identify AR activation inhibitors, including a group of structurally related compounds comprising celastrol, gedunin, and derivatives. To develop an in silico approach for target pathway identification, we apply a gene expression-based analysis that classifies HSP90 inhibitors as having similar activity to celastrol and gedunin. Validating this prediction, we demonstrate that celastrol and gedunin inhibit HSP90 activity and HSP90 clients, including AR. Broadly, this work identifies new modes of HSP90 modulation through a gene expression-based strategy.",

keywords = "CELLCYCLE, CHEMBIO",

author = "Haley Hieronymus and Justin Lamb and Ross, {Kenneth N.} and Peng, {Xiao P.} and Cristina Clement and Anna Rodina and Maria Nieto and Jinyan Du and Kimberly Stegmaier and Raj, {Srilakshmi M.} and Maloney, {Katherine N.} and Jon Clardy and Hahn, {William C.} and Gabriela Chiosis and Golub, {Todd R.}",

note = "Funding Information: We thank Jane Jiang, James Griffin, Azam Mohammad, and George Daley for Ba/F3 cell lines and Phil Febbo for use of microarray data from androgen-stimulated and -deprived LNCaP cells. hHSP90 H9010, Hop F5, and p23 JJ3 antibodies were a generous gift from David O. Toft. This work was supported by a Damon Runyon fellowship to H.H. and NIH and HHMI grants to T.R.G. In compliance with HMS guidelines, we disclose that W.C.H. is a consultant for Novartis Pharmaceuticals, Inc. ",

year = "2006",

month = oct,

doi = "10.1016/j.ccr.2006.09.005",

language = "English (US)",

volume = "10",

pages = "321--330",

journal = "Cancer Cell",

issn = "1535-6108",

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T1 - Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators

AU - Hieronymus, Haley

AU - Lamb, Justin

AU - Ross, Kenneth N.

AU - Peng, Xiao P.

AU - Clement, Cristina

AU - Rodina, Anna

AU - Nieto, Maria

AU - Du, Jinyan

AU - Stegmaier, Kimberly

AU - Raj, Srilakshmi M.

AU - Maloney, Katherine N.

AU - Clardy, Jon

AU - Hahn, William C.

AU - Chiosis, Gabriela

AU - Golub, Todd R.

N1 - Funding Information: We thank Jane Jiang, James Griffin, Azam Mohammad, and George Daley for Ba/F3 cell lines and Phil Febbo for use of microarray data from androgen-stimulated and -deprived LNCaP cells. hHSP90 H9010, Hop F5, and p23 JJ3 antibodies were a generous gift from David O. Toft. This work was supported by a Damon Runyon fellowship to H.H. and NIH and HHMI grants to T.R.G. In compliance with HMS guidelines, we disclose that W.C.H. is a consultant for Novartis Pharmaceuticals, Inc.

PY - 2006/10

Y1 - 2006/10

N2 - Although androgen receptor (AR)-mediated signaling is central to prostate cancer, the ability to modulate AR signaling states is limited. Here we establish a chemical genomic approach for discovery and target prediction of modulators of cancer phenotypes, as exemplified by AR signaling. We first identify AR activation inhibitors, including a group of structurally related compounds comprising celastrol, gedunin, and derivatives. To develop an in silico approach for target pathway identification, we apply a gene expression-based analysis that classifies HSP90 inhibitors as having similar activity to celastrol and gedunin. Validating this prediction, we demonstrate that celastrol and gedunin inhibit HSP90 activity and HSP90 clients, including AR. Broadly, this work identifies new modes of HSP90 modulation through a gene expression-based strategy.

AB - Although androgen receptor (AR)-mediated signaling is central to prostate cancer, the ability to modulate AR signaling states is limited. Here we establish a chemical genomic approach for discovery and target prediction of modulators of cancer phenotypes, as exemplified by AR signaling. We first identify AR activation inhibitors, including a group of structurally related compounds comprising celastrol, gedunin, and derivatives. To develop an in silico approach for target pathway identification, we apply a gene expression-based analysis that classifies HSP90 inhibitors as having similar activity to celastrol and gedunin. Validating this prediction, we demonstrate that celastrol and gedunin inhibit HSP90 activity and HSP90 clients, including AR. Broadly, this work identifies new modes of HSP90 modulation through a gene expression-based strategy.

KW - CELLCYCLE

KW - CHEMBIO

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JO - Cancer Cell

JF - Cancer Cell

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ER -

Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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