J Cancer Prev.  2015 Mar;20(1):5-11. 10.15430/JCP.2015.20.1.5.

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

• Seo YH

• KMID: 2171313
• DOI: http://doi.org/10.15430/JCP.2015.20.1.5

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 1alpha, 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.

Keyword

Heat shock protein 90; Protein-protein interaction; Small molecule; Antagonists & Inhibitors

MeSH Terms

Adenosine Triphosphate
Drug Design
Eukaryotic Cells
Heat-Shock Proteins*
Hot Temperature*
Humans
Matrix Metalloproteinase 2
Molecular Chaperones
Proto-Oncogene Proteins c-akt
Receptor, Epidermal Growth Factor
Adenosine Triphosphate
Heat-Shock Proteins
Matrix Metalloproteinase 2
Molecular Chaperones
Proto-Oncogene Proteins c-akt
Receptor, Epidermal Growth Factor