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 ..
Table of Contents
Target
| Sequence: Hsf1 protein [Mus musculus] Protein Family: heat shock factor Gene:HSF1 Related Protein 3D Structures |
Depositor Specified Assays
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| AID | Name | Type | Comment |
|---|---|---|---|
| 435004 | Luminescence Cell-Based Dose Retest to Identify Potentiators of Heat Shock Factor 1 (HSF1) | confirmatory | 1953 cherrypick compounds at dose in HSF-Luc measuring activity |
| 602296 | Sustained Induction of HSF-1 Measured in Cell-Based System Using Plate Reader - 2038-07_Activator_Dose_CherryPick_Activity | confirmatory | |
| 504408 | Heat Shock Factor-1 (HSF-1) Measured in Cell-Based System Using Plate Reader - 2038-01_Activator_SinglePoint_HTS_Activity | screening | |
| 602280 | Rescue of BEM3 Toxicity in Yeast Measured in Microorganism System Using Plate Reader - 2038-12_Activator_Dose_DryPowder_Activity | confirmatory | |
| 602273 | Rescue of Alpha-Synuclein Toxicity in Yeast Measured in Microorganism System Using Plate Reader - 2038-04_Activator_Dose_CherryPick_Activity | confirmatory | |
| 602279 | Rescue of Alpha-Synuclein Toxicity in Yeast Measured in Microorganism System Using Plate Reader - 2038-04_Activator_Dose_DryPowder_Activity | confirmatory | |
| 624441 | On Hold | ||
| 624442 | On Hold | ||
| 624444 | On Hold | ||
| 624445 | On Hold |
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
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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