scholarly journals Spotlight on the microbes that produce heat shock protein 90-targeting antibiotics

Open Biology ◽  
2012 ◽  
Vol 2 (12) ◽  
pp. 120138 ◽  
Author(s):  
Peter W. Piper ◽  
Stefan H. Millson
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Binding Site ◽  
Cancer Progression ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Cancer Drug ◽  
Atp Binding ◽  
Hsp90 Inhibition ◽  
Atp Binding Site

Heat shock protein 90 (Hsp90) is a promising cancer drug target as a molecular chaperone critical for stabilization and activation of several of the oncoproteins that drive cancer progression. Its actions depend upon its essential ATPase, an activity fortuitously inhibited with a very high degree of selectivity by natural antibiotics: notably the actinomycete-derived benzoquinone ansamycins (e.g. geldanamycin) and certain fungal-derived resorcyclic acid lactones (e.g. radicicol). The molecular interactions made by these antibiotics when bound within the ADP/ATP-binding site of Hsp90 have served as templates for the development of several synthetic Hsp90 inhibitor drugs. Much attention now focuses on the clinical trials of these drugs. However, because microbes have evolved antibiotics to target Hsp90, it is probable that they often exploit Hsp90 inhibition when interacting with each other and with plants. Fungi known to produce Hsp90 inhibitors include mycoparasitic, as well as plant-pathogenic, endophytic and mycorrhizal species. The Hsp90 chaperone may, therefore, be a prominent target in establishing a number of mycoparasitic (interfungal), fungal pathogen–plant and symbiotic fungus–plant relationships. Furthermore the Hsp90 family proteins of the microbes that produce Hsp90 inhibitor antibiotics are able to reveal how drug resistance can arise by amino acid changes in the highly conserved ADP/ATP-binding site of Hsp90.

scholarly journals Mebendazole’s Conformational Space and its Predicted Binding to Human Heat-Shock Protein 90

2021 ◽  
Author(s):  
Walter Fiedler ◽  
Fabian Freisleben ◽  
Jasmin Wellbrock ◽  
Karl Kirschner
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Binding Site ◽  
Leukemia Cell ◽  
Heat Shock Protein 90 ◽  
Md Simulations ◽  
Conformational Space ◽  
Atp Binding ◽  
Atp Binding Site ◽  
Experimental Crystal

Recent experimental evidence suggest that mebendazole, a popular antiparasitic drug, binds to heat shock protein 90 (Hsp90) and inhibit acute myeloid leukemia cell growth. In this study we use quantum mechanics (QM), molecular similarity and molecular dynamics (MD) calculations to predict possible binding poses of mebendazole to the adenosine triphosphate (ATP) binding site of Hsp90. Extensive conformational searches and minimization of the five tautomers of mebendazole using MP2/aug-cc-pVTZ theory level resulting in 152 minima being identified. Mebendazole-Hsp90 complex models were created using the QM optimized conformations and protein coordinates obtained from experimental crystal structures that were chosen through similarity calculations. Nine different poses were identified from a total of 600 ns of explicit solvent, all-atom MD simulations using two different force fields. All simulations support the hypothesis that mebendazole is able to bind to the ATP binding site of Hsp90.

scholarly journals Binding of Natural and Synthetic Inhibitors to Human Heat Shock Protein 90 and Their Clinical Application

Medicina ◽  
2011 ◽  
Vol 47 (8) ◽  
pp. 413 ◽  
Author(s):  
Vilma Petrikaitė ◽  
Daumantas Matulis
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Cancer Progression ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Titration Calorimetry ◽  
Binding Assays ◽  
Hsp90 Inhibitors ◽  
Lead Compounds ◽  
Binding Energetics

This review describes the recent progress in the field of heat shock protein 90 (Hsp90) inhibitor design. Hsp90 is a heat shock protein with a molecular weight of approximately 90 kDa. Hsp90 is considered a good anticancer target because its inhibition leads to inactivation of its numerous client proteins participating in various signaling and other processes involved in cancer progression. Numerous Hsp90 inhibitors-leads currently tested in clinical trials are presented in this review. Furthermore, this review emphasizes the application of biophysical binding assays in the development of Hsp90 inhibitors. The binding of designed lead compounds to various Hsp90 constructs is measured by isothermal titration calorimetry and thermal shift assay. These assays provide a detailed energetic insight of the binding reaction, including the enthalpy, entropy, heat capacity, and the Gibbs free energy. A detailed description of the binding energetics helps to extend our knowledge of structure-activity relationships in the design of more potent inhibitors. The most active compounds are then tested for their absorption, distribution, metabolism, elimination, toxicity, and activity against cancer cell lines.

scholarly journals Heat shock protein 90 inhibition sensitizes acute myelogenous leukemia cells to cytarabine

Blood ◽  
2005 ◽  
Vol 106 (1) ◽  
pp. 318-327 ◽  
Author(s):  
Ruben A. Mesa ◽  
David Loegering ◽  
Heather L. Powell ◽  
Karen Flatten ◽  
Sonnet J. H. Arlander ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Acute Myelogenous Leukemia ◽  
Nucleoside Analogs ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
S Phase ◽  
Myelogenous Leukemia ◽  
Hsp90 Inhibition ◽  
Acute Myelogenous

Previous studies demonstrated that ataxia telangiectasia mutated– and Rad3-related (ATR) kinase and its downstream target checkpoint kinase 1 (Chk1) facilitate survival of cells treated with nucleoside analogs and other replication inhibitors. Recent results also demonstrated that Chk1 is depleted when cells are treated with heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). The present study examined the effects of 17-AAG and its major metabolite, 17-aminogeldanamycin (17-AG), on Chk1 levels and cellular responses to cytarabine in human acute myelogenous leukemia (AML) cell lines and clinical isolates. Cytarabine, at concentrations as low as 30 nM, caused activating phosphorylation of Chk1, loss of the phosphatase Cdc25A, and S-phase slowing. Conversely, treatment with 100 to 300 nM 17-AAG for 24 hours caused Chk1 depletion that was accompanied by diminished cytarabine-induced S-phase accumulation, decreased Cdc25A degradation, and enhanced cytotoxicity as measured by inhibition of colony formation and induction of apoptosis. Additional studies demonstrated that small inhibitory RNA (siRNA) depletion of Chk1 also sensitized cells to cytarabine, whereas disruption of the phosphatidylinositol 3-kinase (PI3k) signaling pathway, which is also blocked by Hsp90 inhibition, did not. Collectively, these results suggest that treatment with 17-AAG might represent a means of reversing checkpoint-mediated cytarabine resistance in AML.

scholarly journals Synergism of Heat Shock Protein 90 and Histone Deacetylase Inhibitors in Synovial Sarcoma

Sarcoma ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-10 ◽  
Author(s):  
Anne Nguyen ◽  
Le Su ◽  
Belinda Campbell ◽  
Neal M. Poulin ◽  
Torsten O. Nielsen
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Synovial Sarcoma ◽  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Therapeutic Benefit ◽  
Multiple Time

Current systemic therapies have little curative benefit for synovial sarcoma. Histone deacetylase (HDAC) inhibitors and the heat shock protein 90 (Hsp90) inhibitor 17-AAG have recently been shown to inhibit synovial sarcoma in preclinical models. We tested combinations of 17-AAG with the HDAC inhibitor MS-275 for synergism by proliferation and apoptosis assays. The combination was found to be synergistic at multiple time points in two synovial sarcoma cell lines. Previous studies have shown that HDAC inhibitors not only induce cell death but also activate the survival pathway NF-κB, potentially limiting therapeutic benefit. As 17-AAG inhibits activators of NF-κB, we tested if 17-AAG synergizes with MS-275 through abrogating NF-κB activation. In our assays, adding 17-AAG blocks NF-κB activation by MS-275 and siRNA directed against histone deacetylase 3 (HDAC3) recapitulates the effects of MS-275. Additionally, we find that the NF-κB inhibitor BAY 11-7085 synergizes with MS-275. We conclude that agents inhibiting NF-κB synergize with HDAC inhibitors against synovial sarcoma.

2-Aroylquinoline-5,8-diones as potent anticancer agents displaying tubulin and heat shock protein 90 (HSP90) inhibition

2016 ◽  
Vol 14 (2) ◽  
pp. 716-723 ◽  
Author(s):  
Kunal Nepali ◽  
Sunil Kumar ◽  
Hsiang-Ling Huang ◽  
Fei-Chiao Kuo ◽  
Cheng-Hsin Lee ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Anticancer Agents ◽  
Heat Shock Protein 90 ◽  
Scaffold Hopping ◽  
Hsp90 Inhibition

This study reports the synthesis of a series of 2-aroylquinoline-5,8-diones (11–23) on the basis of scaffold hopping.

Heat shock protein 90 inhibitors attenuate LPS-induced endothelial hyperpermeability

2008 ◽  
Vol 294 (4) ◽  
pp. L755-L763 ◽  
Author(s):  
Anuran Chatterjee ◽  
Connie Snead ◽  
Gunay Yetik-Anacak ◽  
Galina Antonova ◽  
Jingmin Zeng ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Heat Shock ◽  
Lung Injury ◽  
Heat Shock Protein ◽  
Adherens Junction ◽  
Heat Shock Protein 90 ◽  
Hsp90 Inhibitor ◽  
Barrier Dysfunction ◽  
Focal Adhesion Protein ◽  
Endothelial Hyperpermeability

Endothelial hyperperme ability leading to vascular leak is an important consequence of sepsis and sepsis-induced lung injury. We previously reported that heat shock protein (hsp) 90 inhibitor pretreatment improved pulmonary barrier dysfunction in a murine model of sepsis-induced lung injury. We now examine the effects of hsp90 inhibitors on LPS-mediated endothelial hyperpermeability, as reflected in changes in transendothelial electrical resistance (TER) of bovine pulmonary arterial endothelial cells (BPAEC). Vehicle-pretreated cells exposed to endotoxin exhibited a concentration-dependent decrease in TER, activation of pp60Src, phosphorylation of the focal adhesion protein paxillin, and reduced expression of the adherens junction proteins, vascular endothelial (VE)-cadherin and β-catenin. Pretreatment with the hsp90 inhibitor, radicicol, prevented the decrease in TER, maintained VE-cadherin and β-catenin expression, and inhibited activation of pp60Src and phosphorylation of paxillin. Similarly, when BPAEC hyperpermeability was induced by endotoxin-activated neutrophils, pretreatment of neutrophils and/or endothelial cells with radicicol protected against the activated neutrophil-induced decrease in TER. Increased paxillin phosphorylation and decreased expression of β-catenin and VE-cadherin were also observed in mouse lungs 12 h after intraperitoneal endotoxin and attenuated in mice pretreated with radicicol. These results suggest that hsp90 plays an important role in sepsis-associated endothelial barrier dysfunction.

Effect of heat-shock protein-90 (HSP90) inhibition on human hepatocytes and on liver regeneration in experimental models

Surgery ◽  
2010 ◽  
Vol 147 (5) ◽  
pp. 704-712 ◽  
Author(s):  
Christina Hackl ◽  
Akira Mori ◽  
Christian Moser ◽  
Sven A. Lang ◽  
Rania Dayoub ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Liver Regeneration ◽  
Heat Shock Protein 90 ◽  
Experimental Models ◽  
Human Hepatocytes ◽  
Hsp90 Inhibition
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