Correlation between chemotype-dependent binding conformations of HSP90α/β and isoform selectivity—Implications for the structure-based design of HSP90α/β selective inhibitors for treating neurodegenerative diseases

Ernst, Justin T.; Liu, Mengmeng; Zuccola, Harmon; Neubert, Thomas A.; Beaumont, Kevin; Turnbull, Amy; Kallel, Adam; Vought, Bryan W.; Stamos, Dean

doi:10.1016/j.bmcl.2013.11.036

Cited by 55 publications

(86 citation statements)

References 24 publications

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“…Such chemical tools with a high degree of selectivity for HSP90α/β [86, 88] and GRP94 [32] may pave the way for a better understanding of the biological role of these paralogs in specific disease contexts, as they enable parsing out their function in the context of an un-engineered human cell [32]. They may also enable the identification of disease states where inhibition of a specific HSP90 paralog may be more therapeutically advantageous than inhibition of all HSP90s.…”

Section: Ligands Targeting the Major Chaperonesmentioning

confidence: 99%

“…Taking advantage of these distinctions, especially in the conformational flexibility of an amino acid sequence (Figure 2B, the amino acid sequence is INNLGTIA shown in red) in the N-terminal binding pocket of HSP90α, Ernst et al developed a ligand selective for HSP90α/β [86]. This sequence is identical for HSP90α and β but differs in the first two amino acids in GRP94 (VK) and TRAP1 (VS) [88]. Testing a diverse set of HSP90 inhibitor chemotypes they noted that the compounds that use the α-helical binding conformation of HSP90α ( i.e.…”

Section: No Two Hsp Inhibitors Are the Samementioning

confidence: 99%

“…Testing a diverse set of HSP90 inhibitor chemotypes they noted that the compounds that use the α-helical binding conformation of HSP90α ( i.e. BIIB021 and SNX-2112 analogs) show the highest degree of selectivity against GRP94 and TRAP1 [88]. Using a structure-based approach they prepared novel benzolactam derivatives that were able to access this conformation (Figure 2B) of HSP90α resulting in selective low nanomolar Hsp90 α/β inhibitors (>1000 fold selective vs. GRP94 and TRAP1) [86].…”

Section: No Two Hsp Inhibitors Are the Samementioning

confidence: 99%

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Selective targeting of the stress chaperome as a therapeutic strategy

Taldone

Ochiana

Patel

et al. 2014

Trends in Pharmacological Sciences

104

137

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Normal cellular function is maintained by coordinated proteome machinery that performs a vast array of activities. Helping the proteome in such roles is the chaperome, a network of molecular chaperones and folding enzymes. The stressed cell contains, at any time, a complex mixture of chaperome complexes; a majority performs “housekeeping functions” similarly to non-stressed, normal cells, but a finely-tuned fraction buffers the proteome altered by chronic stress. The stress chaperome is epigenetically distinct from its normal, housekeeping counterpart, providing a basis for its selective targeting by small molecules. Here we discuss development of chaperome inhibitors, and how agents targeting chaperome members in stressed cells are in fact being directed towards chaperome complexes and their effect is therefore determined by their ability to sample and engage such complexes. A new approach is needed to target and implement chaperome modulators in the investigation of diseases, and we propose that the classical thinking in drug discovery needs adjustment when developing chaperome-targeting drugs.

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Section: Ligands Targeting the Major Chaperonesmentioning

confidence: 99%

Section: No Two Hsp Inhibitors Are the Samementioning

confidence: 99%

Section: No Two Hsp Inhibitors Are the Samementioning

confidence: 99%

See 1 more Smart Citation

Selective targeting of the stress chaperome as a therapeutic strategy

Taldone

Ochiana

Patel

et al. 2014

Trends in Pharmacological Sciences

104

137

View full text Add to dashboard Cite

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“…Hsp90 silencing, however, reduced the levels of mutant Htt in both full-length and N-terminal forms, in cellular models, supporting the hypothesis that Htt is an Hsp90 client protein, and that preventing its cycling with Hsp90 promotes its degradation [131,132]. Further supporting this hypothesis is the fact that both wild-type and mutant N-terminal Htt, and full-length mutant Htt were found to interact with Hsp90 [131].…”

Section: Genetic Modulation Of Molecular Chaperones In Hdmentioning

confidence: 83%

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

2016

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Polyglutamine expansion mutations in specific proteins underlie the pathogenesis of a group of progressive neurodegenerative disorders, including Huntington's disease, spinal and bulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and several spinocerebellar ataxias. The different mutant proteins share ubiquitous expression and abnormal proteostasis, with misfolding and aggregation, but nevertheless evoke distinct patterns of neurodegeneration. This highlights the relevance of the full protein context where the polyglutamine expansion occurs, and suggests different interactions with the cellular proteostasis machinery. Molecular chaperones are key elements of the proteostasis machinery and therapeutic targets for neurodegeneration. Here we provide a focused review on Hsp90, Hsp70, and their cochaperones, and how their genetic or pharmacological modulation affects the proteostasis and disease phenotypes in cellular and animal models of polyglutamine disorders. The emerging picture is that, in principle, Hsp70 modulation may be more amenable for long-term treatment by promoting a more selective clearance of mutant proteins than Hsp90 modulation, which may further decrease the necessary wild-type counterparts. It seems, nevertheless, unlikely that a single Hsp70 modulator will benefit all polyglutamine diseases. Indeed, available data, together with insights from effects on tau and alpha-synuclein in models of Alzheimer's and Parkinson's diseases, indicates that Hsp70 modulators may lead to different effects on the proteostasis of different mutant and wild-type client proteins. Future studies should include the further development of isoform selective inhibitors, namely to avoid off-target effects on Hsp in the mitochondria, and their characterization in distinct polyglutamine disease models to account for client protein-specific differences.

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“…Thus, an 8-residue amino acid sequence present within the N-terminal binding pocket of Hsp90α and β, which differs in the first two amino acids of the corresponding sequence in both GRP94 and TRAP1, contributed to the stability of chemotype-induced conformations of the Hsp90α and β isoforms, resulting in a higher level of Hsp90α/β selectivity compared with GRP94 and TRAP1 (.1,000-fold). 74,115,116 Similarly, insertion of several purine-scaffold class chemical compounds into a new allosteric pocket, arising from the conformational flexibility of GRP94, led to the development of the purine-based ligands, PU-H54 and PU-WS13, that were .100-fold more selective for GRP94 over Hsp90α/β and TRAP1. 74,117 Another GRP94-specific ligand, NECA …”

Section: Hsp90 Paralog-selective Ligandsmentioning

confidence: 99%

Hsp90 as a therapeutic target in endocrinology: current evidence

Ratajczak¹,

Ward²,

Walsh³

et al. 2015

RRED

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Abstract:The ability of heat shock protein 90 (Hsp90) to modulate many growth and signaling pathways simultaneously makes it an attractive target in the field of cancer therapeutics and provided the initial impetus for significant efforts over the past decade to identify Hsp90 inhibitors, several of which are now showing promise in the clinic for cancer treatment. The four known human Hsp90 members are compartmentalized: Hsp90α and β in the cytoplasm, GRP94 in the endoplasmic reticulum, and TRAP1 in the mitochondrial matrix. While these isoforms share a similar N-terminal domain adenosine triphosphate-binding pocket, structural variations allow unique interactions for inhibitors targeting this binding site, providing an avenue for the development of paralog-selective drugs with different biological effects applicable therapeutically to a wide range of diseases. At the same time, the conformational flexibility of the Hsp90 molecular chaperone has unveiled multiple small-molecule target sites within all subdomains of the protein, greatly expanding opportunities for viable drug development. This review summarizes the function, expression, and clinical significance of the Hsp90 isoforms and elaborates on the inhibitors and modulators that impact Hsp90 chaperone activity. Finally, the review focuses on the therapeutic utility of a range of Hsp90-modulating agents in the treatment of specific diseases associated with the endocrine system.

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Correlation between chemotype-dependent binding conformations of HSP90α/β and isoform selectivity—Implications for the structure-based design of HSP90α/β selective inhibitors for treating neurodegenerative diseases

Cited by 55 publications

References 24 publications

Selective targeting of the stress chaperome as a therapeutic strategy

Selective targeting of the stress chaperome as a therapeutic strategy

Modulation of Molecular Chaperones in Huntington’s Disease and Other Polyglutamine Disorders

Hsp90 as a therapeutic target in endocrinology: current evidence

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