Structure-based design of 7-carbamate analogs of geldanamycin

Rastelli, Giulio; Tian, Zong-Qiang; Wang, Zhan; Myles, David C.; Liu, Yaoquan

doi:10.1016/j.bmcl.2005.08.013

Cited by 42 publications

(33 citation statements)

References 18 publications

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“…Hsp90 interacts with large portions of ER LBD and sequences of the receptor required for stable DNA binding (Chambraud et al, 1990). 17-DMAG inhibited the function of Hsp90, thus decreasing the protein levels of ER (Rastelli et al, 2005; Schulte et al, 1998). Since CHIP is a co-chaperone of Hsp90 for protein degradation and folding (Dickey et al, 2007; McDonough and Patterson, 2003), and CHIP interacts with the N-terminal AF-1 domain of ERβ (Tateishi et al, 2006), it is very likely that CHIP, Hsp90 and ERβ form a ternary complex.…”

Section: Resultsmentioning

confidence: 98%

Reciprocal Regulation of ERα and ERβ Stability and Activity by Diptoindonesin G

Zhao

Wang

James

et al. 2015

Chemistry & Biology

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Summary ERβ is regarded as a “tumor suppressor” in breast cancer due to its anti-proliferative effects. However, unlike ERα, ERβ has not been developed as a therapeutic target in breast cancer due to loss of ERβ in aggressive cancers. In a small molecule library screen for ERβ stabilizers, we identified Diptoindonesin G (Dip G) which significantly increases ERβ protein stability, while decreasing ERα protein levesl. Dip G enhances the transcription and anti-proliferative activities of ERβ, while attenuating the transcription and proliferative effects of ERα. Further investigation revealed that instead of targeting ER, Dip G targets the CHIP E3 ubiquitin ligase shared by ERα and ERβ. Thus, Dip G is a dual functional moiety that reciprocally controls ERα and ERβ protein stability and activities via an indirect mechanism. The ERβ stabilization effects of Dip G may enable the development of ERβ-targeted therapies for human breast cancers.

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Section: Resultsmentioning

confidence: 98%

Reciprocal Regulation of ERα and ERβ Stability and Activity by Diptoindonesin G

Zhao

Wang

James

et al. 2015

Chemistry & Biology

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“…These water molecules are known to play a crucial role in ligand binding to Hsp90. 42,43 Docking Docking calculations were performed with the Induced Fit Docking 36,44 protocol available in the Schrödinger 2014-1 suite 36 with default settings. Complexes were visually inspected (up to 20 topscoring complexes per ligand) and a representative binding mode was selected within the top scoring ones.…”

Section: Ligand and Protein Preparationmentioning

confidence: 99%

Computational Polypharmacology Analysis of the Heat Shock Protein 90 Interactome

Anighoro

Stumpfe

Heikamp

et al. 2015

J. Chem. Inf. Model.

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The design of a single drug molecule that is able to simultaneously and specifically interact with multiple biological targets is gaining major consideration in drug discovery. However, the rational design of drugs with a desired polypharmacology profile is still a challenging task, especially when these targets are distantly related or unrelated. In this work, we present a computational approach aimed at the identification of suitable target combinations for multitarget drug design within an ensemble of biologically relevant proteins. The target selection relies on the analysis of activity annotations present in molecular databases and on ligand-based virtual screening. A few target combinations were also inspected with structure-based methods to demonstrate that the identified dual-activity compounds are able to bind target combinations characterized by remote binding site similarities. Our approach was applied to the heat shock protein 90 (Hsp90) interactome, which contains several targets of key importance in cancer. Promising target combinations were identified, providing a basis for the computational design of compounds with dual activity. The approach may be used on any ensemble of proteins of interest for which known inhibitors are available.

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“…Figure 2A shows the key hydrogen bonding interactions between GM and yeast Hsp90 31. Of particular note are those of the carbamate group, which is essential for activity32,33 and stabilizes the complex through direct and indirect bonding with Leu34, Asp79, Gly83 and Thr171.…”

Section: Inhibitor Classesmentioning

confidence: 99%

Discovery and development of heat shock protein 90 inhibitors

Taldone

Sun

Chiosis

2009

Bioorganic & Medicinal Chemistry

158

128

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Heat shock protein 90 (Hsp90) is an important target in cancer because of its role in maintaining transformation and has recently become the focus of several drug discovery and development efforts. While compounds with different modes of action are known, the focus of this review is on those classes of compounds which inhibit Hsp90 by binding to the N-terminal ATP pocket. These include natural product inhibitors such as geldanamycin and radicicol and synthetic inhibitors comprised of purines, pyrazoles, isoxazoles and other scaffolds. The synthetic inhibitors have been discovered either by structure-based design, high throughput screening and more recently using fragment-based design and virtual screening techniques. This review will discuss the discovery of these different classes, as well as their development as potential clinical agents.

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Structure-based design of 7-carbamate analogs of geldanamycin

Cited by 42 publications

References 18 publications

Reciprocal Regulation of ERα and ERβ Stability and Activity by Diptoindonesin G

Reciprocal Regulation of ERα and ERβ Stability and Activity by Diptoindonesin G

Computational Polypharmacology Analysis of the Heat Shock Protein 90 Interactome

Discovery and development of heat shock protein 90 inhibitors

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