Alternate Strategies of Hsp90 Modulation for the Treatment of Cancer and Other Diseases

Brandt, Gary E. L.; Blagg, Brian S. J.

doi:10.2174/156802609789895683

Cited by 45 publications

(42 citation statements)

References 158 publications

(183 reference statements)

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“…This review has been limited to ATP-competitive inhibitors that target the nucleotide-binding pocket and a discussion on molecules which inhibit Hsp90 by alternative mechanisms is beyond the scope of this review. Readers interested in learning about these alternative modes of Hsp90 inhibition are referred to earlier review articles on this topic [18,29,30]. …”

Section: Hsp90 Inhibitorsmentioning

confidence: 99%

Protein chaperones: a composition of matter review (2008 – 2013)

Taldone

Patel

Bolaender

et al. 2014

Expert Opinion on Therapeutic Patents

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Introduction Heat shock proteins (Hsps) are proteins with important functions in regulating disease phenotypes. Historically, Hsp90 has first received recognition as a target in cancer, with consequent efforts extending its potential role to other diseases. Hsp70 has also attracted interest as a therapeutic target for its role as a co-chaperone to Hsp90 as well as its own anti-apoptotic roles. Areas covered Herein, patents from 2008 to 2013 are reviewed to identify those that disclose composition of matter claimed to inhibit Hsp90 or Hsp70. Expert opinion For Hsp90, there has been considerable creativity in the discovery of novel pharmacophores that fall outside the three initially discovered scaffolds (i.e., ansamycins, resorcinols and purines). Nonetheless, much of the patent literature appears to build on previously reported structure activity relationship through slight modifications of Hsp90 inhibitor space by finding weaknesses in existing patents. The major goal of future development of Hsp90 inhibitors is not necessarily identifying better molecules but rather understanding how to rationally use these agents in the clinic. The development of Hsp70 inhibitors has lagged behind. It will require a more concerted effort from the drug discovery community in order to begin to realize the potential of this target.

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Section: Hsp90 Inhibitorsmentioning

confidence: 99%

Protein chaperones: a composition of matter review (2008 – 2013)

Taldone

Patel

Bolaender

et al. 2014

Expert Opinion on Therapeutic Patents

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“…Hsp90 functions together with multiple co-chaperones to maintain the integrity of a wide variety of client proteins and is essential for cellular homeostasis and viability (Li and Buchner, 2013; Sreedhar et al, 2004; Taipale et al, 2010). Modulation of Hsp90 function exhibits therapeutic potential for cancer and other diseases including cystic fibrosis, viral infections and neurodegenerative diseases (Brandt and Blagg, 2009; Mayer et al, 2009; Taipale et al, 2010). Structurally, Hsp90 proteins consist of three ordered domains, the N-terminal domain (NTD), middle domain (MD) and C-terminal domain (CTD), connected by flexible linker regions.…”

Section: Introductionmentioning

confidence: 99%

In Vivo Conformational Dynamics of Hsp90 and Its Interactors

Chavez

Schweppe

Eng

et al. 2016

Cell Chemical Biology

133

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Summary Hsp90 belongs to a family of some of the most highly expressed heat shock proteins that function as molecular chaperones to protect the proteome not only from the heat shock, but from other misfolding events. As many client proteins of Hsp90 are involved in oncogenesis, this chaperone has been in focus of intense research efforts. Yet, we lack structural information for how Hsp90 interacts with co-chaperones and client proteins. Here, we develop a mass spectrometry based approach that allows quantitative measurements of in vitro and in vivo effects of small molecule inhibitors on Hsp90 conformation, and interaction with co-chaperones and client proteins. From this analysis we were able to derive structural models for how Hsp90 engages its interaction partners in vivo and how different drugs affect these structures. Additionally, the methodology described here offers a new approach to probe the effects of virtually any inhibitor treatment on the proteome level.

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“…Here we report that Hsp90 controls HIV-1 reactivation from latency by modulating the NF-κB pathway, and hence is a key molecule coupling T-cell activation to HIV-1 reactivation. Inhibitors of Hsp90 are in phase II clinical trials to treat cancer and are being considered to treat neurodegenerative diseases and cystic fibrosis (16). On the other hand, physiological processes, such as fever, can induce Hsp90.…”

mentioning

confidence: 99%

Heat shock protein 90 controls HIV-1 reactivation from latency

Anderson

Low

Weston

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

108

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Significance Antiretroviral therapy cannot eradicate HIV-1 because the virus can become transcriptionally inactive in resting memory CD4+ T cells (and other cell types), which are long-lived, thus generating a reservoir undetectable by the immune system. When therapy is stopped, the latent viral reservoir is activated and HIV-1 rebounds. Our understanding of HIV-1 latency and reactivation is incomplete. Here we report that the heat shock protein 90 (Hsp90) regulates HIV-1 reactivation from latency by controlling the NF-kB pathway. Therefore Hsp90 is a key molecule linking HIV-1 reactivation from latency to CD4+ T-cell activation. Selective Hsp90 inhibitors combined with PKC-ϑ inhibitors, all in phase II clinical trials, potently suppressed HIV-1 reactivation, thus Hsp90 may be a novel target to control HIV-1 latency.

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Alternate Strategies of Hsp90 Modulation for the Treatment of Cancer and Other Diseases

Cited by 45 publications

References 158 publications

Protein chaperones: a composition of matter review (2008 – 2013)

Protein chaperones: a composition of matter review (2008 – 2013)

In Vivo Conformational Dynamics of Hsp90 and Its Interactors

Heat shock protein 90 controls HIV-1 reactivation from latency

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