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BioAssay: AID 2119

Summary of Probe Development Efforts to Identify Inhibitors of Glycogen Synthase Kinase-3 beta (GSK-3b)

The serine/threonine kinase glycogen synthase kinase-3 beta (GSK-3b) is a known master regulator for several cellular pathways that include insulin signaling and glycogen synthesis, neurotrophic factor signaling, Wnt signaling, neurotransmitter signaling and microtubule dynamics. Consequently, this enzyme has a critical role in metabolism, transcription, development, cell survival, and neuronal more ..
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AID: 2119
Data Source: Broad Institute (2046_INHIBITORS)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
Deposit Date: 2009-11-09
Target
Sequence: glycogen synthase kinase 3 beta isoform 1 [Homo sapiens]
Description ..   
Protein Family: Protein Kinases, catalytic domain

Gene:GSK3B     Related Protein 3D Structures     More BioActivity Data..
Depositor Specified Assays
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AIDNameTypeComment
2097Cell-Free Homogeneous Primary HTS to Identify Inhibitors of GSK3beta Activityscreeningprimary screen
623979Inhibition of Human CDK5 Activity Measured in Biochemical System Using Microfluidics - 2046-12_Inhibitor_Dose_DryPowder_Activity_Set2confirmatory
623998GSK3beta Measured in Biochemical System Using Plate Reader - 2046-01_Inhibitor_Dose_DryPowder_Activityconfirmatory
624027GSK3beta Assay at Varied ATP concentrations Measured in Biochemical System Using Plate Reader - 2046-04_Inhibitor_Dose_DryPowder_Activityconfirmatory
624088PathHunter bCatenin (U2-OS) Measured in Cell-Based System Using Plate Reader - 2133-06_Inhibitor_Dose_DryPowder_Activityconfirmatory
624091Dose responses of selected compounds against GSK3b Measured in Biochemical System Using Plate Reader - 2133-10_Inhibitor_Dose_DryPowder_Activityother
623989Inhibition of Human GSK3 beta Activity Measured in Biochemical System Using Microfluidics - 2046-10_Inhibitor_Dose_DryPowder_Activity_Set2confirmatory
624076Kinome profiling single dose point Measured in Biochemical System Using Plate Reader - 2133-09_Inhibitor_SinglePoint_DryPowder_Activityother
624108GSK3beta Surface Plasmon Resonance (SPR) Assay Measured in Biochemical System Using Microfluidics - 2133-08_Inhibitor_Dose_DryPowder_Activityother
623978Inhibition of Human GSK3 alpha Activity Measured in Biochemical System Using Microfluidics - 2046-11_Inhibitor_Dose_DryPowder_Activity_Set2confirmatory
624086TCF/LEF Reporter Assay Measured in Cell-Based System Using Plate Reader - 2133-01_Inhibitor_Dose_DryPowder_Activityconfirmatory
434947Luminescence Cell-Free Homogeneous Counter Screen to Identify Inhibitors of ADP-glo Reagentsconfirmatory
434954Luminescence Cell-Free Homogeneous Dose Retest to Identify Inhibitors of Glycogen Synthase Kinase-3 beta Activityconfirmatory
623999CDK5 Measured in Biochemical System Using Plate Reader - 2046-05_Inhibitor_Dose_DryPowder_Activityconfirmatory
624057Human p-Tau and Total Tau ELISA Measured in Cell-Based System Using Plate Reader - 2133-07_Inhibitor_Dose_DryPowder_Activityconfirmatory
Description:
Biological Relevance:

The serine/threonine kinase glycogen synthase kinase-3 beta (GSK-3b) is a known master regulator for several cellular pathways that include insulin signaling and glycogen synthesis, neurotrophic factor signaling, Wnt signaling, neurotransmitter signaling and microtubule dynamics. Consequently, this enzyme has a critical role in metabolism, transcription, development, cell survival, and neuronal functions and has been implicated in multiple human disorders including Alzheimer's disease, bipolar disorder, noninsulin-dependent diabetes mellitus, cardiac hypertrophy, and cancer. Thus, highly selective small molecule modulators are needed to help elucidate GSK3b function and regulation. The majority of the existing chemical inhibitors compete for the ATP-binding site of GSK-3b and inhibit additional kinases, while the two known structural series of ATP-noncompetitive inhibitors have low potency and suboptimal pharmacological properties that limit their use. Small molecules targeting the allosteric sites of GSK-3b could have the potential to provide highly specific GSK-3b inhibitors that may help elucidate GSK-3b function and regulation.

Project Goal:
The glycogen synthase kinase-3 beta (GSK-3b) is a known master regulator for several cellular pathways and plays a critical role in metabolism, transcription, development, cell survival, and neuronal functions. The overall objective is to identify one or multiple series of inhibitors of GSK-3beta with micromolar potency. Such compounds will become probe(s) with demonstrated kinase-selectivity (≥fold IC50) and activation of Wnt signaling (EC50 < 10uM) and desired effect on neuronal morphology. Structural series that demonstrates non-ATP competitive mechanism of action will be strongly preferred.

Keywords: GSK3beta, kinase, inhibition, HTS

Primary Collaborators: BJennifer Pan, jpan@broadinstitute.org, Broad Institute, Cambridge, MA
Additional Information
Grant Number: 1 R03 MH087442-01

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