scholarly journals Inhibition of Histone Deacetylase 6 Acetylates and Disrupts the Chaperone Function of Heat Shock Protein 90

2005 ◽  
Vol 280 (29) ◽  
pp. 26729-26734 ◽  
Author(s):  
Purva Bali ◽  
Michael Pranpat ◽  
James Bradner ◽  
Maria Balasis ◽  
Warren Fiskus ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Histone Deacetylase ◽  
Heat Shock Protein 90 ◽  
Histone Deacetylase 6 ◽  
Chaperone Function

Dual Targeting Strategies On Histone Deacetylase 6 (HDAC6) And Heat Shock Protein 90 (Hsp90)

2021 ◽  
Vol 28 ◽  
Author(s):  
Davide Bonanni ◽  
Andrea Citarella ◽  
Davide Moi ◽  
Luca Pinzi ◽  
Elisa Bergamini ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Histone Deacetylase ◽  
Single Molecule ◽  
Heat Shock Protein 90 ◽  
Histone Deacetylase 6 ◽  
Small Molecular Weight ◽  
Antitumor Effects ◽  
Target Drug ◽  
Dual Inhibitors

: The design of multi-target drugs acting simultaneously on multiple signaling pathways is a growing field in medicinal chemistry, especially for the treatment of complex diseases such as cancer. Histone deacetylase 6 (HDAC6) is an established anticancer drug target involved in tumor cells transformation. Being an epigenetic enzyme at the interplay of many biological processes, HDAC6 has become an attractive target for polypharmacology studies aimed at improving therapeutic efficacy of anticancer drugs. For example, the molecular chaperone Heat shock protein 90 (Hsp90) is a substrate of HDAC6 deacetylation, and several lines of evidence demonstrate that simultaneous inhibition of HDAC6 and Hsp90 promote synergistic antitumor effects on different cancer cell lines, highlighting the potential benefits of developing a single molecule endowed with multi-target activity. This review will summarize the complex interplay between HDAC6 and Hsp90, providing also useful hints for multi-target drug design and discovery approaches in this field. To this end, crystallographic structures of HDAC6 and Hsp90 complexes will be extensively reviewed in the light of discussing binding pockets features and pharmacophore requirements and providing useful guidelines for the design of dual inhibitors. The few examples of multi-target inhibitors obtained so far, mostly based on chimeric approaches, will be summarized and put into context. Finally, the main features of HDAC6 and Hsp90 inhibitors will be compared, and ligand- and structure-based strategies potentially useful for the development of small molecular weight dual inhibitors will be proposed and discussed.

scholarly journals Design of Dual Inhibitors of Histone Deacetylase 6 and Heat Shock Protein 90

ACS Omega ◽  
2020 ◽  
Vol 5 (20) ◽  
pp. 11473-11480 ◽  
Author(s):  
Luca Pinzi ◽  
Rosaria Benedetti ◽  
Lucia Altucci ◽  
Giulio Rastelli
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Histone Deacetylase ◽  
Heat Shock Protein 90 ◽  
Histone Deacetylase 6 ◽  
Dual Inhibitors

scholarly journals Histone Deacetylase 6 and Heat Shock Protein 90 Control the Functions of Foxp3+ T-Regulatory Cells

2011 ◽  
Vol 31 (10) ◽  
pp. 2066-2078 ◽  
Author(s):  
E. F. de Zoeten ◽  
L. Wang ◽  
K. Butler ◽  
U. H. Beier ◽  
T. Akimova ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Histone Deacetylase ◽  
T Regulatory Cells ◽  
Heat Shock Protein 90 ◽  
Regulatory Cells ◽  
Histone Deacetylase 6

scholarly journals Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function

2015 ◽  
Vol 309 (12) ◽  
pp. L1410-L1419 ◽  
Author(s):  
Atul D. Joshi ◽  
Nektarios Barabutis ◽  
Charalampos Birmpas ◽  
Christiana Dimitropoulou ◽  
Gagan Thangjam ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Heat Shock ◽  
Lung Injury ◽  
Heat Shock Protein ◽  
Histone Deacetylase ◽  
Heat Shock Protein 90 ◽  
Selective Inhibitor ◽  
Endothelial Barrier ◽  
Rhoa Activity ◽  
Chaperone Function

Transendothelial hyperpermeability caused by numerous agonists is dependent on heat shock protein 90 (Hsp90) and leads to endothelial barrier dysfunction (EBD). Inhibition of Hsp90 protects and restores transendothelial permeability. Hyperacetylation of Hsp90, as by inhibitors of histone deacetylase (HDAC), suppresses its chaperone function and mimics the effects of Hsp90 inhibitors. In this study we assessed the role of HDAC in mediating lipopolysaccharide (LPS)-induced transendothelial hyperpermeability and acute lung injury (ALI). We demonstrate that HDAC inhibition protects against LPS-mediated EBD. Inhibition of multiple HDAC by the general inhibitors panobinostat or trichostatin provided protection against LPS-induced transendothelial hyperpermeability, acetylated and suppressed Hsp90 chaperone function, and attenuated RhoA activity and signaling crucial to endothelial barrier function. Treatment with the HDAC3-selective inhibitor RGFP-966 or the HDAC6-selective inhibitor tubastatin A provided partial protection against LPS-mediated transendothelial hyperpermeability. Similarly, knock down of HDAC3 and HDAC6 by specific small-interfering RNAs provided significant protection against LPS-induced EBD. Furthermore, combined pharmacological inhibition of both HDAC3 and -6 attenuated the inflammation, capillary permeability, and structural abnormalities associated with LPS-induced ALI in mice. Together these data indicate that HDAC mediate increased transendothelial hyperpermeability caused by LPS and that inhibition of HDAC protects against LPS-mediated EBD and ALI by suppressing Hsp90-dependent RhoA activity and signaling.

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.

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