Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90 Journal Article
| Authors: | He, H.; Zatorska, D.; Kim, J.; Aguirre, J.; Llauger, L.; She, Y.; Wu, N.; Immormino, R. M.; Gewirth, D. T.; Chiosis, G. |
| Article Title: | Identification of potent water soluble purine-scaffold inhibitors of the heat shock protein 90 |
| Abstract: | Hsp90 is a chaperone protein that allows cancer cells to tolerate the many components of dysregulated pathways. Its inactivation may result in targeting multiple molecular alterations and, thus, in reverting the transformed phenotype. The PU-class, a purine-scaffold Hsp90 inhibitor series, has been reported to be potent and selective against Hsp90 both in vitro and in vivo models of cancer. Here, a series of this class was synthesized and evaluated as inhibitors of the chaperone. The structure-activity relationship and selectivity for tumor Hsp90 of compounds within the series is presented. The study identifies water soluble derivatives (> 5 mM in PBS pH 7.4) of nanomolar potency (IC 50 ∼ 50 nM) in cellular and animal models of cancer. Binding affinities of these compounds for Hsp90 correlate well with their biological activities. When administered in vivo to mice bearing MDA-MB-468 human breast cancer xenografted tumors, these agents result in pharmacologically relevant concentrations and, accordingly, in modulation of Hsp90-client proteins in tumors. © 2006 American Chemical Society. |
| Keywords: | controlled study; unclassified drug; nonhuman; binding affinity; cell proliferation; animal cell; mouse; breast cancer; animal experiment; animal model; drug potency; drug structure; tumor xenograft; drug screening assays, antitumor; cell line, tumor; drug selectivity; structure activity relation; structure-activity relationship; heat shock protein 90 inhibitor; heat shock protein 90; hsp90 heat-shock proteins; purines; molecular structure; water; drug binding; solubility; drug solubility; 8 (6 bromobenzo[1,3]dioxol 5 ylsulfanyl) 9 (3 isopropylaminopropyl)adenine |
| Journal Title: | Journal of Medicinal Chemistry |
| Volume: | 49 |
| Issue: | 1 |
| ISSN: | 0022-2623 |
| Publisher: | American Chemical Society |
| Date Published: | 2006-01-12 |
| Start Page: | 381 |
| End Page: | 390 |
| Language: | English |
| DOI: | 10.1021/jm0508078 |
| PUBMED: | 16392823 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 72" - "Export Date: 4 June 2012" - "CODEN: JMCMA" - "Source: Scopus" |
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