Heat shock protein 90 (Hsp90)/Histone deacetylase (HDAC) dual inhibitors for the treatment of azoles-resistant Candida albicans

2021 ◽  
pp. 113961
Author(s):  
Chaochen Li ◽  
Jie Tu ◽  
Guiyan Han ◽  
Na Liu ◽  
Chunquan Sheng
Keyword(s):  
Candida Albicans ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Histone Deacetylase ◽  
Heat Shock Protein 90 ◽  
Dual Inhibitors

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 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.

Discovery and Optimization of 4,5-Diarylisoxazoles as Potent Dual Inhibitors of Pyruvate Dehydrogenase Kinase and Heat Shock Protein 90

2014 ◽  
Vol 57 (23) ◽  
pp. 9832-9843 ◽  
Author(s):  
Tao Meng ◽  
Dadong Zhang ◽  
Zuoquan Xie ◽  
Ting Yu ◽  
Shuchao Wu ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Pyruvate Dehydrogenase ◽  
Heat Shock Protein 90 ◽  
Pyruvate Dehydrogenase Kinase ◽  
Dual Inhibitors

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

Multiple-Target Drugs: Inhibitors of Heat Shock Protein 90 and of Histone Deacetylase

2005 ◽  
Vol 6 (3) ◽  
pp. 337-351 ◽  
Author(s):  
A. Budillon ◽  
F. Bruzzese ◽  
E. Gennaro ◽  
M. Caraglia
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Histone Deacetylase ◽  
Heat Shock Protein 90 ◽  
Multiple Target
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