Gene expression signature-based chemical genomic prediction identifies a novel class of HSP90 pathway modulators Journal Article
| Authors: | 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. |
| Article 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. © 2006 Elsevier Inc. All rights reserved. |
| Keywords: | signal transduction; controlled study; unclassified drug; human cell; drug activity; genetic analysis; reproducibility of results; phenotype; cell survival; gene expression; gene expression profiling; protein targeting; tumor markers, biological; cell line; receptor, epidermal growth factor; high throughput screening; cell line, tumor; structure activity relation; prostatic neoplasms; chembio; regulatory mechanism; rna, messenger; cell culture techniques; protein induction; heat shock protein 90 inhibitor; heat shock protein 90; hsp90 heat-shock proteins; chemical genetics; androgen receptor; cellcycle; bicalutamide; receptors, androgen; antibiotics, antineoplastic; inhibitory concentration 50; fusion proteins, bcr-abl; genome, human; benzoquinones; lactams, macrocyclic; structural genomics; metribolone; drug identification; triterpenes; fms-like tyrosine kinase 3; gedunin; celastrol; 3 alpha hydroxydeoxodihydrogedunin; 3 deoxo 3beta acetoxydeoxydihydrogedunin; 7 desacetoxy 6,7 dehydrogedunin; deacetoxy 7 oxogedunin; deacetylgedunin; deoxodeoxydihydrogedunin; deoxygedunin; dihydro 7 desacetyldeoxygedunin; dihydrocelastrol; dihydrocelastryl diacetate; pristimerol; limonins |
| Journal Title: | Cancer Cell |
| Volume: | 10 |
| Issue: | 4 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2006-10-01 |
| Start Page: | 321 |
| End Page: | 330 |
| Language: | English |
| DOI: | 10.1016/j.ccr.2006.09.005 |
| PUBMED: | 17010675 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 152" - "Export Date: 4 June 2012" - "CODEN: CCAEC" - "Source: Scopus" |
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