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BioAssay: AID 2118

Identifying Small Molecules To Probe the Role of Heat Shock Factor 1 in Cancer

The heat shock response (HSR) is a powerful transcriptional program which acts genome-wide, not only to restore the normal protein folding environment through the induction of heat shock proteins (HSP) such as HSP70 and HSP90, but as more recent work has shown to re-shape global cellular pathways controlling survival, growth and metabolism. In mammals, this ancient response is regulated primarily more ..
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AID: 2118
Data Source: Broad Institute (2038_INHIBITORS)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2009-11-09
Modify Date: 2010-03-26
Target
Depositor Specified Assays
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AIDNameTypeComment
2098Luminescence Cell-Based Primary HTS to Identify Inhibitors of Heat Shock Factor 1 (HSF1).screeningprimary screen
2382Luminescence Cell-Based Dose Confimation HTS to Identify Inhibitors of Heat Shock Factor 1 (HSF1)confirmatory
602268Heat Shock Factor-1 (HSF-1) Luciferase Reporter Measured in Cell-Based System Using Plate Reader - 2038-01_Inhibitor_Dose_DryPowder_Activityconfirmatory
493085HSF-1 induced GFP reporter and Doxycycline induced RFP reporter Measured in Cell-Based System Using Plate Reader - 2038-03_Inhibitor_DoseNoFile_CherryPick_Internal-Standard_Set3confirmatory
602266Quantitative-PCR analysis for transcription inhibition of HSF-1 target gene Hsp90aa Measured in Cell-Based System Using RT-PCR - 2038-08_Inhibitor_Dose_CherryPick_Activityconfirmatory
602269HSF-1 induced GFP reporter and Doxycycline induced RFP reporter Measured in Cell-Based System Using Plate Reader - 2038-03_Inhibitor_Dose_DryPowder_Activityconfirmatory
588827HSF-1 induced GFP reporter and Doxycycline induced RFP reporter Measured in Cell-Based System Using Plate Reader - 2038-03_Inhibitor_Dose_CherryPick_Activity_Set4confirmatory
588847Luciferase Inhibition Counter Screen Measured in Biochemical System Using Plate Reader - 2038-06_Inhibitor_Dose_CherryPick_Activityconfirmatory
493083HSF-1 induced GFP reporter and Doxycycline induced RFP reporter Measured in Cell-Based System Using Plate Reader - 2038-03_Inhibitor_DoseNoFile_CherryPick_Activity_Set3confirmatory
Description:
Biological Relevance:

The heat shock response (HSR) is a powerful transcriptional program which acts genome-wide, not only to restore the normal protein folding environment through the induction of heat shock proteins (HSP) such as HSP70 and HSP90, but as more recent work has shown to re-shape global cellular pathways controlling survival, growth and metabolism. In mammals, this ancient response is regulated primarily by Heat Shock Factor 1 (HSF-1), a transcription factor whose mode of action has been conserved in broad outline across all eukaryotes. Acting at a global systems level, HSF-1 function permits cells to survive the drastic imbalances in signaling and profound alterations in DNA, protein and energy metabolism that occur during malignant transformation. Knockdown of HSF-1 expression using genetic techniques is well tolerated in normal cells and even in whole animals but, malignant cells display a profound dependence on this "non-oncogene." The regulation of HSF-1 function is complex and involves a cascade of multiple post-translational modifications that may provide biologically interesting and therapeutically tractable targets for specific inhibition of HSF-1 function. We propose to identify specific inhibitors of HSF-1 activation to further probe its role in cancer biology.

Project Goal:

None of the currently available inhibitors of HSF-1 activation has been shown to act upon HSF1 directly and all of these compounds
demonstrate prominent non-HSF1 dependent effects unique to their particular modes of action. Hence, the limited specificity, poorly defined mechanisms of action and possible effects as general transcription and translation inhibitors rather than as specific HSF-1 inhibitors highlight the unmet need for the identification of more specific inhibitors of HSF-1. Therefore, this project seeks to identify specific inhibitors of HSF1 using an optimized high throughput cell-based reporter gene assay. Then to evaluate the potency, specificity and mode of action of compounds using secondary and counter-screening assays in order to guide the selection of screen hits for analog synthesis and support their optimization into useful chemical biological probes.

Probe attributes:
a. IC50 < 10uM
b. Specific inhibitor of HSF-1, not a general transcription or translation inhibitor. We would like to see 10-fold or greater specific inhibition over general transcription inhibition or translation.
c. Non-luciferase quenching.
d. Minimal cytotoxicity to non-transformed cells at 5-fold the concentration determined to inhibit HSF1 activation by 50% (IC50)
e. Inhibition of cancer cell growth/survival with 10-fold greater potency than the growth/survival of non-cancer cells
f. Inhibition of oncogene-mediated foci formation

Keywords: HSF-1, Heat Shock Response, Cancer

Primary Collaborators : Luke Whitesell, Whitehead Inst., whitesell@wi.mit.edu, 617-452-3542, Cambridge, MA,
Additional Information
Grant Number: 1 R03 MH086465-01

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