scholarly journals Post-translational modification and conformational state of Heat Shock Protein 90 differentially affect binding of chemically diverse small molecule inhibitors

Oncotarget ◽  
2013 ◽  
Vol 4 (7) ◽  
pp. 1065-1074 ◽  
Author(s):  
Kristin Beebe ◽  
Mehdi Mollapour ◽  
Bradley Scroggins ◽  
Chrisostomos Prodromou ◽  
Wanping Xu ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Heat Shock Protein 90 ◽  
Conformational State ◽  
Post Translational Modification

scholarly journals Detection of the ATPase Activity of the Molecular Chaperones Hsp90 and Hsp72 Using the Transcreener™ ADP Assay Kit

2010 ◽  
Vol 15 (3) ◽  
pp. 279-286 ◽  
Author(s):  
Martin Rowlands ◽  
Craig McAndrew ◽  
Chris Prodromou ◽  
Laurence Pearl ◽  
Andrew Kalusa ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Atpase Activity ◽  
Small Molecule ◽  
Drug Target ◽  
Small Molecule Inhibitors ◽  
Heat Shock Protein 90 ◽  
Cancer Drug ◽  
Cell Growth Inhibition ◽  
Client Proteins

The molecular chaperone heat shock protein 90 (Hsp90) is required for the correct folding and stability of a number of client proteins that are important for the growth and maintenance of cancer cells. Heat shock protein 72 (Hsp72), a co-chaperone of Hsp90, is also emerging as an attractive cancer drug target. Both proteins bind and hydrolyze adenosine triphosphate (ATP), and ATPase activity is essential for their function. Inhibition of Hsp90 ATPase activity leads to the degradation of client proteins, resulting in cell growth inhibition and apoptosis. Several small-molecule inhibitors of the ATPase activity of Hsp90 have been described and are currently being evaluated clinically for the treatment of cancer. A number of methods for the measurement of ATPase activity have been previously used, but not all of these are ideally suited to screening cascades in drug discovery projects. The authors have evaluated the use of commercial reagents (Transcreener™ ADP) for the measurement of ATPase activity of both yeast and human Hsp90 (ATP Km ~500 µM) and human Hsp72 (ATP Km ~1 µM). The low ATPase activity of human Hsp90 and its stimulation by the co-chaperone Aha1 was measured with ease using reduced incubation times, generating robust data (Z′ = 0.75). The potency of several small-molecule inhibitors of both Hsp90 and Hsp72 was determined using the Transcreener™ reagents and compared well to that determined using other assay formats.

scholarly journals Small Molecule Inhibitors Targeting the Heat Shock Protein System of Human Obligate Protozoan Parasites

2019 ◽  
Vol 20 (23) ◽  
pp. 5930 ◽  
Author(s):  
Zininga ◽  
Shonhai
Keyword(s):  
Heat Shock ◽  
Heat Shock Proteins ◽  
Heat Shock Protein ◽  
Small Molecule ◽  
Molecular Chaperones ◽  
Small Molecule Inhibitors ◽  
Protozoan Parasites ◽  
Obligate Intracellular ◽  
Human Host ◽  
Shock Proteins

Obligate protozoan parasites of the kinetoplastids and apicomplexa infect human cells to complete their life cycles. Some of the members of these groups of parasites develop in at least two systems, the human host and the insect vector. Survival under the varied physiological conditions associated with the human host and in the arthropod vectors requires the parasites to modulate their metabolic complement in order to meet the prevailing conditions. One of the key features of these parasites essential for their survival and host infectivity is timely expression of various proteins. Even more importantly is the need to keep their proteome functional by maintaining its functional capabilities in the wake of physiological changes and host immune responses. For this reason, molecular chaperones (also called heat shock proteins)—whose role is to facilitate proteostasis—play an important role in the survival of these parasites. Heat shock protein 90 (Hsp90) and Hsp70 are prominent molecular chaperones that are generally induced in response to physiological stress. Both Hsp90 and Hsp70 members are functionally regulated by nucleotides. In addition, Hsp70 and Hsp90 cooperate to facilitate folding of some key proteins implicated in cellular development. In addition, Hsp90 and Hsp70 individually interact with other accessory proteins (co-chaperones) that regulate their functions. The dependency of these proteins on nucleotide for their chaperone function presents an Achille’s heel, as inhibitors that mimic ATP are amongst potential therapeutic agents targeting their function in obligate intracellular human parasites. Most of the promising small molecule inhibitors of parasitic heat shock proteins are either antibiotics or anticancer agents, whose repurposing against parasitic infections holds prospects. Both cancer cells and obligate human parasites depend upon a robust protein quality control system to ensure their survival, and hence, both employ a competent heat shock machinery to this end. Furthermore, some inhibitors that target chaperone and co-chaperone networks also offer promising prospects as antiparasitic agents. The current review highlights the progress made so far in design and application of small molecule inhibitors against obligate intracellular human parasites of the kinetoplastida and apicomplexan kingdoms.

Application of Target-Mediated Drug Disposition Model to Small Molecule Heat Shock Protein 90 Inhibitors

2013 ◽  
Vol 41 (6) ◽  
pp. 1285-1294 ◽  
Author(s):  
Shinji Yamazaki ◽  
Zhongzhou Shen ◽  
Ying Jiang ◽  
Bill J. Smith ◽  
Paolo Vicini
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Small Molecule ◽  
Drug Disposition ◽  
Heat Shock Protein 90 ◽  
Target Mediated Drug Disposition ◽  
Disposition Model

Abstract 3771: Identification of novel small molecule inhibitors of the inducible heat shock protein Hsp70

2011 ◽  
Author(s):  
Gregor M. Balaburski ◽  
Julie Leu ◽  
Seth A. Hayik ◽  
Mark Andrake ◽  
Roland Dunbrack ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Heat Shock Protein Hsp70

Small-Molecule Targeting of Heat Shock Protein 90 Chaperone Function:  Rational Identification of a New Anticancer Lead

2006 ◽  
Vol 49 (26) ◽  
pp. 7721-7730 ◽  
Author(s):  
Massimiliano Meli ◽  
Marzia Pennati ◽  
Maria Curto ◽  
Maria Grazia Daidone ◽  
Janet Plescia ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Small Molecule ◽  
Heat Shock Protein 90 ◽  
Chaperone Function

scholarly journals Discovery and validation of small-molecule heat-shock protein 90 inhibitors through multimodality molecular imaging in living subjects

2012 ◽  
Vol 109 (37) ◽  
pp. E2476-E2485 ◽  
Author(s):  
C. T. Chan ◽  
R. E. Reeves ◽  
R. Geller ◽  
S. S. Yaghoubi ◽  
A. Hoehne ◽  
...  
Keyword(s):  
Molecular Imaging ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Small Molecule ◽  
Heat Shock Protein 90
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