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Small Molecule Inhibitors to Disrupt Protein-protein Interactions of Heat Shock Protein 90 Chaperone Machinery.

Seo YH - J Cancer Prev (2015)

Bottom Line: To discover small molecule inhibitors targeting Hsp90 chaperone machinery, several strategies have been employed, which results in three classes of inhibitors such as N-terminal inhibitors, C-terminal inhibitors, and inhibitors disrupting protein-protein interactions of Hsp90 chaperone machinery.The lack of well-defined binding pocket and starting points for drug design challenges medicinal chemists to discover small molecule inhibitors disrupting protein-protein interactions of Hsp90.The present review will focus on the current studies on small molecule inhibitors disrupting protein-protein interactions of Hsp90 chaperone machinery, provide biological background on the structure, function and mechanism of Hsp90's protein-protein interactions, and discuss the challenges and promise of its small molecule modulations.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Keimyung University, Daegu, Korea.

ABSTRACT
Heat shock protein 90 (Hsp90) is an adenosine triphosphate dependent molecular chaperone in eukaryotic cells that regulates the activation and maintenance of numerous regulatory and signaling proteins including epidermal growth factor receptor, human epidermal growth factor receptor 2, mesenchymal-epithelial transition factor, cyclin-dependent kinase-4, protein kinase B, hypoxia-inducible factor 1α, and matrix metalloproteinase-2. Since many of Hsp90 clients are oncogenic proteins, Hsp90 has become an attractive therapeutic target for treatment of cancer. To discover small molecule inhibitors targeting Hsp90 chaperone machinery, several strategies have been employed, which results in three classes of inhibitors such as N-terminal inhibitors, C-terminal inhibitors, and inhibitors disrupting protein-protein interactions of Hsp90 chaperone machinery. Developing small molecule inhibitors that modulate protein-protein interactions of Hsp90 is a challenging task, although it offers many alternative opportunities for therapeutic intervention. The lack of well-defined binding pocket and starting points for drug design challenges medicinal chemists to discover small molecule inhibitors disrupting protein-protein interactions of Hsp90. The present review will focus on the current studies on small molecule inhibitors disrupting protein-protein interactions of Hsp90 chaperone machinery, provide biological background on the structure, function and mechanism of Hsp90's protein-protein interactions, and discuss the challenges and promise of its small molecule modulations.

No MeSH data available.


Related in: MedlinePlus

Schematic illustration of Hsp90-Hop-Hsp70 folding relay system. TPR, tetratricopeptide repeat; Hsp, heat shock protein.
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f2-jcp-20-05: Schematic illustration of Hsp90-Hop-Hsp70 folding relay system. TPR, tetratricopeptide repeat; Hsp, heat shock protein.

Mentions: Hsp organizing protein (Hop) is an abundant, highly conserved eukaryotic protein that mediates the association of the molecular chaperones, Hsp90 and Hsp70.33,34 The current consensus model for Hsp90 mediated protein folding assumes that a newly synthesized polypeptide is first chaperoned by Hsp70 and then transferred to Hsp90 for the correct folding and maturation (Fig. 2). To do so, Hsp70 and Hsp90 are brought into close proximity, via their interactions with Hop. C-terminal peptides of Hsp70 and Hsp90 independently interact with two tetratricopeptide repeat (TPR) domains of Hop, TPR1 and TPR2A respectively, and form a multichaperone complex of Hsp70-Hop-Hsp90.33,34 If Hsp90 is blocked to interact with TPR2A domain of Hop, a multichaperone complex of Hsp70-Hop-Hsp90 can no longer form. Besides, mounting evidence has demonstrated that the interaction of Hsp90 with Hop via the TPR2A is critically essential for Hsp90 chaperoning function. Therefore, the blockage of Hsp70-Hop-Hsp90 folding relay system will lead to the ubiquitination and proteasomal degradation of Hsp90 client proteins.


Small Molecule Inhibitors to Disrupt Protein-protein Interactions of Heat Shock Protein 90 Chaperone Machinery.

Seo YH - J Cancer Prev (2015)

Schematic illustration of Hsp90-Hop-Hsp70 folding relay system. TPR, tetratricopeptide repeat; Hsp, heat shock protein.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4384710&req=5

f2-jcp-20-05: Schematic illustration of Hsp90-Hop-Hsp70 folding relay system. TPR, tetratricopeptide repeat; Hsp, heat shock protein.
Mentions: Hsp organizing protein (Hop) is an abundant, highly conserved eukaryotic protein that mediates the association of the molecular chaperones, Hsp90 and Hsp70.33,34 The current consensus model for Hsp90 mediated protein folding assumes that a newly synthesized polypeptide is first chaperoned by Hsp70 and then transferred to Hsp90 for the correct folding and maturation (Fig. 2). To do so, Hsp70 and Hsp90 are brought into close proximity, via their interactions with Hop. C-terminal peptides of Hsp70 and Hsp90 independently interact with two tetratricopeptide repeat (TPR) domains of Hop, TPR1 and TPR2A respectively, and form a multichaperone complex of Hsp70-Hop-Hsp90.33,34 If Hsp90 is blocked to interact with TPR2A domain of Hop, a multichaperone complex of Hsp70-Hop-Hsp90 can no longer form. Besides, mounting evidence has demonstrated that the interaction of Hsp90 with Hop via the TPR2A is critically essential for Hsp90 chaperoning function. Therefore, the blockage of Hsp70-Hop-Hsp90 folding relay system will lead to the ubiquitination and proteasomal degradation of Hsp90 client proteins.

Bottom Line: To discover small molecule inhibitors targeting Hsp90 chaperone machinery, several strategies have been employed, which results in three classes of inhibitors such as N-terminal inhibitors, C-terminal inhibitors, and inhibitors disrupting protein-protein interactions of Hsp90 chaperone machinery.The lack of well-defined binding pocket and starting points for drug design challenges medicinal chemists to discover small molecule inhibitors disrupting protein-protein interactions of Hsp90.The present review will focus on the current studies on small molecule inhibitors disrupting protein-protein interactions of Hsp90 chaperone machinery, provide biological background on the structure, function and mechanism of Hsp90's protein-protein interactions, and discuss the challenges and promise of its small molecule modulations.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Keimyung University, Daegu, Korea.

ABSTRACT
Heat shock protein 90 (Hsp90) is an adenosine triphosphate dependent molecular chaperone in eukaryotic cells that regulates the activation and maintenance of numerous regulatory and signaling proteins including epidermal growth factor receptor, human epidermal growth factor receptor 2, mesenchymal-epithelial transition factor, cyclin-dependent kinase-4, protein kinase B, hypoxia-inducible factor 1α, and matrix metalloproteinase-2. Since many of Hsp90 clients are oncogenic proteins, Hsp90 has become an attractive therapeutic target for treatment of cancer. To discover small molecule inhibitors targeting Hsp90 chaperone machinery, several strategies have been employed, which results in three classes of inhibitors such as N-terminal inhibitors, C-terminal inhibitors, and inhibitors disrupting protein-protein interactions of Hsp90 chaperone machinery. Developing small molecule inhibitors that modulate protein-protein interactions of Hsp90 is a challenging task, although it offers many alternative opportunities for therapeutic intervention. The lack of well-defined binding pocket and starting points for drug design challenges medicinal chemists to discover small molecule inhibitors disrupting protein-protein interactions of Hsp90. The present review will focus on the current studies on small molecule inhibitors disrupting protein-protein interactions of Hsp90 chaperone machinery, provide biological background on the structure, function and mechanism of Hsp90's protein-protein interactions, and discuss the challenges and promise of its small molecule modulations.

No MeSH data available.


Related in: MedlinePlus