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BioAssay: AID 493224

Luminescence Cell-Based Primary HTS to Identify Activators of Heat Shock Factor 1 (HSF1)

The misfolding and aggregation of proteins underlies the pathology of many aging-associated neurodegenerative disorders including Alzheimer's, Huntington's and Parkinson's diseases. Most efforts to treat these diseases have focused on strategies that directly target misfolding of the specific protein thought to underlie pathogenesis in each disorder. Much less effort has been directed at more ..
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AID: 493224
Data Source: Broad Institute (2038-01_ACTIVATORS_SINGLE-POINT_MLPCN-HTS)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2011-02-15
Target
Depositor Specified Assays
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AIDNameTypeComment
435004Luminescence Cell-Based Dose Retest to Identify Potentiators of Heat Shock Factor 1 (HSF1)confirmatory1953 cherrypick compounds at dose in HSF-Luc measuring activity
602296Sustained Induction of HSF-1 Measured in Cell-Based System Using Plate Reader - 2038-07_Activator_Dose_CherryPick_Activityconfirmatory
602280Rescue of BEM3 Toxicity in Yeast Measured in Microorganism System Using Plate Reader - 2038-12_Activator_Dose_DryPowder_Activityconfirmatory
504408Heat Shock Factor-1 (HSF-1) Measured in Cell-Based System Using Plate Reader - 2038-01_Activator_SinglePoint_HTS_Activityscreening
602273Rescue of Alpha-Synuclein Toxicity in Yeast Measured in Microorganism System Using Plate Reader - 2038-04_Activator_Dose_CherryPick_Activityconfirmatory
624445Luminescent Cell-based Secondary Assay to Evaluate the Proteasomal Inhibition Activity of HSF1 Inducers Measured in Cell-Based System Using Plate Reader - 2038-13_Activator_Dose_DryPowder_Activity_Set2confirmatory
602279Rescue of Alpha-Synuclein Toxicity in Yeast Measured in Microorganism System Using Plate Reader - 2038-04_Activator_Dose_DryPowder_Activityconfirmatory
624441Fluorescence Cell-Based assay to Identify Reactive Oxygen Species Inducers in U2OS cells Measured in Cell-Based System Using Plate Reader - 2038-14_Activator_Dose_DryPowder_Activityconfirmatory
624444Luminescent Cell-based Secondary Assay to Evaluate the Proteasomal Inhibition Activity of HSF1 Inducers Measured in Cell-Based System Using Plate Reader - 2038-13_Activator_Dose_DryPowder_Activityconfirmatory
624442Fluorescence Cell-Based assay to Identify Reactive Oxygen Species Inducers in U2OS cells Measured in Cell-Based System Using Plate Reader - 2038-14_Activator_Dose_DryPowder_Activity_Set2confirmatory
Description:
Keywords:
HSF-1, Heat Shock Response, Protein Aggregation, Neurodegenerative Disorders

Project Goal:
The misfolding and aggregation of proteins underlies the pathology of many aging-associated neurodegenerative disorders including Alzheimer's, Huntington's and Parkinson's diseases. Most efforts to treat these diseases have focused on strategies that directly target misfolding of the specific protein thought to underlie pathogenesis in each disorder. Much less effort has been directed at understanding how cells cope with protein misfolding through their endogenous molecular chaperone machinery and why these intrinsic protective mechanisms ultimately fail in the course of disease progression. Stimulation of the ancient cytoprotective heat-shock response increases expression of multiple molecular chaperones, so-called heat-shock proteins (Hsp), each of which assists protein folding and guards against aggregation in complementary, but distinct ways. With the goal of identifying chemical biological probes that stimulate the heat shock response to ameliorate protein aggregation, this HTS project will screen compounds from a structurally diverse library in high throughput fashion using cells stably transduced with a luciferase reporter construct under control of a minimal heat-shock response element. By virtue of their unbiased mode of discovery, the probes identified in this project will provide new insights into how the heat-shock response is regulated at the whole cell level and could provide useful leads for the future development of therapeutics that act in a powerful, previously unexploited way to address the ever increasing burden of aging-associated neurodegenerative disease that confronts our society.

Probe attributes:
a. EC50 <10uM for induction of reporter activity
b. Not luminescent
c. Not broadly chemically reactive (strong electrophile or ROS-generating)
d. Increase in response of heat shock reporter >/=3 Standard Deviation from Mean of DMSO Control at a concentration e. Activates heat shock response by novel biochemical mode of action or ameliorates protein aggregation in one or more whole cell models of aggregation-induced cytotoxicity
Additional Information
Grant Number: 1 R03 MH086465-01

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