An Hsp90 modulator that exhibits a unique mechanistic profile

Ramsey, Deborah M.; McConnell, Jeanette R.; Alexander, Leslie D.; Tanaka, Kaishin W.; Vera, Chester M.; McAlpine, Shelli R.

doi:10.1016/j.bmcl.2012.03.012

Cited by 15 publications

(6 citation statements)

References 30 publications

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“…Proteomics analysis also showed the extent of the generated stress response, suggesting that HSP90 inhibition in cancer could be a double-edged sword if used in the wrong cellular context. As a consequence, several groups are trying to develop inhibitors that either target the C-terminal domain [93–97] or the middle domain [98] or aim at blocking interactions of HSP90 with co-chaperones, e.g. inhibiting interactions with the kinase adapter CDC37 [99–102] or inhibiting the ATPase stimulation by Aha1 [103].…”

Section: Five-year Viewmentioning

confidence: 99%

Proteomic interrogation of HSP90 and insights for medical research

Weidenauer

Wang

Joshi

et al. 2017

Expert Review of Proteomics

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Introduction Heat shock protein 90 (HSP90) regulates protein homeostasis in eukaryotes. As a ‘professional interactor’, HSP90 binds to and chaperones many proteins and has both housekeeping and disease-related functions but its regulation remains in part elusive. HSP90 complexes are a target for therapy, notably against cancer, and several inhibitors are currently in clinical trials. Proteomic studies have revealed the vast interaction network of HSP90 and, in doing so, the extent of cellular processes the chaperone takes part in, especially in yeast and human cells. Furthermore, small-molecule inhibitors were used to probe the global impact of its inhibition on the proteome. Areas covered We review here recent HSP90-related interactomics and total proteome studies and their relevance for research on cancer, neurodegenerative and pathogen diseases. Expert commentary Proteomics experiments are our best chance to identify the context-dependent global proteome of HSP90 and thus uncover and understand its disease-specific biology. However, understanding the complexity of HSP90 will require multiple complementary, quantitative approaches and novel bioinformatics to translate interactions into ordered functional networks and pathways. Developing therapies will necessitate more knowledge on HSP90 complexes and networks with disease relevance and on total proteome changes induced by their perturbation. Most work has been done in cancer, thus a lot remains to be done in the context of other diseases.

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Section: Five-year Viewmentioning

confidence: 99%

Proteomic interrogation of HSP90 and insights for medical research

Weidenauer

Wang

Joshi

et al. 2017

Expert Review of Proteomics

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“…Interestingly, some of these analogs ( 32 and 33 ) manifest anti-proliferative activities without inducing the heat-shock response, a major drawback associated with the parent compounds (Koay et al, 2014; McConnell, Alexander, & McAlpine, 2014). Recently, Ramsey and coworkers reported a novel San A-amide derivative, 34 , which induces apoptosis and interacts with Hsp90 in biochemical pull-down assays, but has no effect on interaction between Hsp90 and C-terminal domain proteins, suggesting a novel mechanism by which it might modulate Hsp90 function (Ramsey et al, 2012). …”

Section: Novel Hsp90 Inhibitors: Beyond the Usual Suspectsmentioning

confidence: 99%

Anticancer Inhibitors of Hsp90 Function

Garg

Khandelwal

Blagg

2016

Advances in Cancer Research

131

109

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The 90-kDa heat-shock protein (Hsp90) is a molecular chaperone responsible for the stability and function of a wide variety of client proteins that are critical for cell growth and survival. Many of these client proteins are frequently mutated and/or overexpressed in cancer cells and are therefore being actively pursued as individual therapeutic targets. Consequently, Hsp90 inhibition offers a promising strategy for simultaneous degradation of several anticancer targets. Currently, most Hsp90 inhibitors under clinical evaluation act by blocking the binding of ATP to the Hsp90 N-terminal domain and thereby, induce the degradation of many Hsp90-dependent oncoproteins. Although, they have shown some promising initial results, clinical challenges such as induction of the heat-shock response, retinopathy, and gastrointestinal tract toxicity are emerging from human trials, which constantly raise concerns about the future development of these inhibitors. Novobiocin derivatives, which do not bind the chaperone’s N-terminal ATPase pocket, have emerged over the past decade as an alternative strategy to inhibit Hsp90, but to date, no derivative has been investigated in the clinical setting. In recent years, a number of natural or synthetic compounds have been identified that modulate Hsp90 function via various mechanisms. These compounds not only offer new chemotypes for the development of future Hsp90 inhibitors but can also serve as chemical probes to unravel the biology of Hsp90. This chapter presents a synopsis of inhibitors that directly, allosterically, or even indirectly alters Hsp90 function, and highlights their proposed mechanisms of action.

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“…In the recent past, mainly the groups of Silverman and McAlpine prepared more than 100 sansalvamide A analogues, both on solid-phase and in solution. Some of those showed excellent chemotherapeutic activities [33,34,35,36,37,38,39].…”

Section: Cyclopentadepsipeptidesmentioning

confidence: 99%

Cyclodepsipeptides: A Rich Source of Biologically Active Compounds for Drug Research

Sivanathan

Scherkenbeck

2014

Molecules

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Abstract:Faced with the need to find new drugs for all kinds of diseases, science sees that Nature offers numerous classes of compounds showing an impressively high biological potential. Among those are the cyclodepsipeptides, hybrid structures composed of amino and hydroxy acids. In the past decades numerous cyclodepsipeptides have been isolated and their potential as drugs has been studied extensively. For several cyclodepsipeptides total syntheses both in solution and on solid-phase have been established, allowing the production of combinatorial libraries. In addition, the biosynthesis of specific cyclodepsipeptides has been elucidated and used for the chemoenzymatic preparation of nonnatural analogues. This review summarizes the recent literature on cyclic tetra-to decadepsipeptides, composed exclusively of α-amino-and α-hydroxy acids.

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An Hsp90 modulator that exhibits a unique mechanistic profile

Cited by 15 publications

References 30 publications

Proteomic interrogation of HSP90 and insights for medical research

Proteomic interrogation of HSP90 and insights for medical research

Anticancer Inhibitors of Hsp90 Function

Cyclodepsipeptides: A Rich Source of Biologically Active Compounds for Drug Research

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