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

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

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 Target-Mediated Brain Tissue Binding for Small Molecule Inhibitors of Heat Shock Protein 90

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1009
Author(s):  
Lassina Badolo ◽  
Kenneth Thirstrup ◽  
Søren Møller Nielsen ◽  
Ask Püschl ◽  
Thomas Jensen ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Brain Tissue ◽  
Small Molecule ◽  
Heat Shock Protein 90 ◽  
Tissue Binding ◽  
Unbound Fraction ◽  
Drug Concentrations ◽  
In Vivo Pharmacokinetics

Drug distribution in the brain is generally associated with an affinity for fatty brain tissues and therefore known to be species- and concentration-independent. We report here the effect of target affinity on brain tissue binding for 10 small molecules designed to inhibit brain heat shock protein 90 (HSP90), a widespread protein whose expression is 1–2% of total cytosolic proteins in eucaryotes. Our results show that increasing the test item concentrations from 0.3 to 100 µM increased the unbound fraction 32-fold for the most potent molecules, with no change for the inactive one (1.1 fold change). Saturation of HSP90 led to normal concentration-independent brain tissue binding. In vivo pharmacokinetics performed in rats showed that the overall volume of distribution of compounds is correlated with their affinity for HSP90. The in vitro binding and in vivo pharmacokinetics (PK) performed in rats showed that small molecule HSP90 inhibitors followed the principle of target-mediated drug disposition. We demonstrate that assessing unbound fractions in brain homogenate was subject to HSP90 target interference; this may challenge the process of linking systemic-free drug concentrations to central nervous system unbound concentrations necessary to establish the proper pharmacokinetics/pharmacodynamics (PK/PD) relation needed for human dose prediction.

Heat Shock Protein 90 (HSP90) Is Overexpressed in Primary and Cultured Hodgkin Lymphoma (HL) Cells: Role of Therapeutic Targeting Using the Small Molecule Inhibitor 17-AAG.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2422-2422
Author(s):  
Georgios V. Georgakis ◽  
Yang Li ◽  
George Z. Rassidakis ◽  
L. Jeffrey Medeiros ◽  
Anas Younes
Keyword(s):  
Cell Cycle ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Cell Cycle Arrest ◽  
Hodgkin Lymphoma ◽  
Small Molecule ◽  
Heat Shock Protein 90 ◽  
Conventional Chemotherapy ◽  
Cycle Arrest ◽  
Molecule Inhibitor

Abstract Conventional chemotherapy is the golden standard for therapy of Hodgkin Lymphoma (HL). Nevertheless, considerable toxicity and secondary malignancies indicate the need for targeted therapy that preferentially kills the malignant cells. The molecular chaperone heat shock protein 90 (HSP90) is expressed in all mammalian cells, but it is overexpressed in malignancy. 17-AAG, a small molecule inhibitor of HSP90, has been shown to induce apoptosis and cell cycle arrest in a variety of tumor types. In the present study we show that HSP90 is overexpressed in the primary Hodgkin and Reed-Sternberg (HRS) cells, as well as in HL derived cells lines. Inhibition of HSP90 17-AAG showed antiproliferative effect in HL derived cell lines in a dose dependent manner. Cell death was due to apoptosis, as determined by Annexin-V staining and FACS analysis. Apoptosis was mediated by the activation of the caspase pathway, especially by caspase 8, 9, and 3. Inhibition of caspase activity by the pancaspase inhibitor Z-VAD-FMK partially reversed the 17-AAG lethal effect. 17-AAG had no significant on the level of the antiapoptotic Bcl-2 family members or the cellular or X-Linked inhibitors of apoptosis. In contrast, there was considerable degradation of cFLIP. Moreover, 17-AAG treatment reduced the intracellular levels of molecules that have been shown to be of key importance in HRS cell survival and proliferation, including AKT and the phosphorylated ERK1/2, but with minimal change in total ERK1/2. Cell cycle arrest was observed at G0/G1 or at G2/M phase, and was mediated by reduction in the levels of MDM2, cyclin D1 with cdk4 and cdk6, and cyclin B1. The potential synergy of 17-AAG with conventional chemotherapy and anti-TRAIL death receptor monoclonal antibody, was explored by the simultaneous incubation of HL derived cells with both doxorubicin or antibodies against TRAIL receptors R1 and R2, respectively. The combination of 17-AAG with doxorubicin or anti-TRAIL antibodies was significantly more effective than either agent alone. Based on these data we are conducting a phase II study of 17-AAG in patients with relapsed classical HL.

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