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BioAssay: AID 2085

Summary assay for inhibitors of HePTP

Protein tyrosine phosphatases (PTPs), working with protein tyrosine kinases (PTKs), control the phosphorylation state of many proteins in the signal transduction pathways. HePTP is a tyrosine phosphatase expressed in hematopoietic cells and regulates the MAP kinases Erk and p38. It has been found that HePTP is often dysregualted in the preleukemic disorder myelodysplastic syndrome, as well as in more ..
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 Tested Compounds
 Tested Compounds
All(2)
 
 
Probe(2)
 
 
Active(2)
 
 
 Tested Substances
 Tested Substances
All(2)
 
 
Probe(2)
 
 
Active(2)
 
 
AID: 2085
Data Source: Burnham Center for Chemical Genomics (BCCG-A257-HePTP-Summary-Assay)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2009-10-29
Modify Date: 2011-01-13

Data Table ( Complete ):           View Active Data    View All Data
Target
BioActive Compounds: Chemical Probe: 2    Active: 2
Related Experiments
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AIDNameTypeComment
521HTS Discovery of Chemical Inhibitors of HePTP, a Leukemia TargetConfirmatorydepositor-specified cross reference: HTS Discovery of Chemical Inhibitors of HePTP, a Leukemia Target
1055In Vitro MKP-3 Dose Response Assay for SAR StudyConfirmatorydepositor-specified cross reference: In Vitro MKP-3 Dose Response Assay for SAR Study
1059In Vitro HePTP Dose Response Colorimetric Assay for SAR StudyConfirmatorydepositor-specified cross reference: In Vitro HePTP Dose Response Colorimetric Assay for SAR Study
1077Fluorescent secondary assay for dose-response confirmation of chemical inhibitors of HePTPConfirmatorydepositor-specified cross reference: Fluorescent secondary assay for dose-response confirmation of chemical inhibitors of HePTP
1957SAR VHR1 Fluorescent Assay for In Vitro dose response studiesConfirmatorydepositor-specified cross reference: SAR VHR1 Fluorescent Assay for In Vitro dose response studies
2068MOA HePTP Fluorescent secondary assay for identification of redox-state modulating compoundsConfirmatorydepositor-specified cross reference: Redox state counter screen of AID 1077
2134HTS HePTP Fluorescent Assay using OMFP substrate for In Vitro dose response studiesConfirmatorydepositor-specified cross reference: Dose response assay
2678SAR analysis of chemical inhibitors of HePTP using a Fluorescent assay - Set 2Confirmatorydepositor-specified cross reference
435032Dose Response confirmation of HTS hits from an HePTP Fluorescent Assay using OMFP substrate - Set 2Confirmatorydepositor-specified cross reference: Dose response assay
449736SAR analysis of compounds that inhibit HePTP - Set 2Confirmatorydepositor-specified cross reference: SAR analysis
488889SAR analysis of compounds that inhibit HePTP - Set 3Confirmatorydepositor-specified cross reference
488923Dose Response confirmation of compounds that inhibit HePTPConfirmatorydepositor-specified cross reference
Description:
Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute (SBMRI, San Diego, CA)
Network: NIH Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Number: XO1 MH077603-01
Assay Provider: Dr. Tomas Mustelin, Sanford-Burnham Medical Research Institute

Protein tyrosine phosphatases (PTPs), working with protein tyrosine kinases (PTKs), control the phosphorylation state of many proteins in the signal transduction pathways. HePTP is a tyrosine phosphatase expressed in hematopoietic cells and regulates the MAP kinases Erk and p38. It has been found that HePTP is often dysregualted in the preleukemic disorder myelodysplastic syndrome, as well as in acute myelogeneous leukemia. Small molecule inhibitors of HePTP will be useful as molecular probes for studying the mechanism of signal transduction and MAP kinase regulation, and may have therapeutic potential for the treatment of hematopoietic malignancies.

This AID summarizes the SBCCG's probe development efforts to identify HePTP inhibitors.

Two potential probes have been identified and probe reports have been submitted describing compound screening.

The identification of probe, CID1357397(ML119) is as follows. From the primary and confirmation screen (AID 521) a candidate was identified for probe development. SAR was developed using the analog-by-catalog approach for this scaffold. Dry powder compounds were purchased and tested in (AID 1077) and confirmed in a counter screen (AID 1059). The selectivity of the probe compound against MKP-3 (AID 1055) and VHR1 (AID 1957) was determined. The compound was active in a cell-based assay assessing the phosphorylation state of Erk MAPK in Jurkat cells performed by the assay provider.

The second probe, CID4302116(ML120) was identified when results of the VHR1 hit counter screens against HePTP and MKP-3 were analyzed. SAR was developed using the analog-by-catalog approach for this scaffold. Dry powder compounds were purchased and tested in (AID 1077). The selectivity of the probe compound against MKP-3 (AID 1055) and VHR1 (AID 1957) was determined. The compound was active in a cell-based assay assessing the phosphorylation state of Erk MAPK in Jurkat cells performed by the assay provider.

Details of protocols, compound structures, and results from the original assays can be found in PubChem at the respective AIDs listed below.
Protocol
Please see pertinent AIDs: 521, 1059, 1077, 1055, 1957, 2068, 2134, 435032, 449736
Comment
Probe molecules are defined as the positives of this assay and assigned a score of 100. Two probes have been identified.
Categorized Comment - additional comments and annotations
From PubChem:
Assay Cell Type: Jurkat
From MLP Probe Report:
Probe count: 2
MLP Probe ML# for probe 1: ML119
PubChem Substance ID (SID) for probe 1: 26514203
PubChem Compound ID (CID) for probe 1: 1357397
Probe type for probe 1: Inhibitor
IC50/EC50 (nM) for probe 1: 235
Target for probe 1: HePTP (gi: 18375660)
Disease relevance for probe 1: Leukemia
Anti-target for probe 1: VHR1, MKP-3
Fold selectivity for probe 1: 5, 21
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK50696/ (ID: 2377196)
Grant number for probe 1: MH077603-01
MLP Probe ML# for probe 2: ML120
PubChem Substance ID (SID) for probe 2: 85176630
PubChem Compound ID (CID) for probe 2: 4302116
Probe type for probe 2: Inhibitor
IC50/EC50 (nM) for probe 2: 1800
Target for probe 2: HePTP (gi: 18375660)
Disease relevance for probe 2: Leukemia
Anti-target for probe 2: VHR1, MKP-3
Fold selectivity for probe 2: 4.3, 11
NCBI Book chapter link for probe 2: http://www.ncbi.nlm.nih.gov/books/NBK50697/ (ID: 2377368)
Grant number for probe 2: MH077603-01
NCBI Book chapter title for probe 1: Selective HePTP Inhibitors: Probe 1
NCBI Book chapter title for probe 2: Selective HePTP Inhibitors: Probe 2
Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1Assay 1: (Qualifier)This qualifier is to be used with the next TID, IC50. If the qualifier is "=", the IC50 result equals the value in that column; if the qualifier is ">", the IC50 result is greater than that valueString
2Assay 1: Fluorescence Confirmation (IC50)(AID 1077)IC50 value determined using sigmoidal dose response equationFloatμM
3Assay 2: (Qualifier)This qualifier is to be used with the next TID, IC50. If the qualifier is "=", the IC50 result equals the value in that column; if the qualifier is ">", the IC50 result is greater than that valueString
4Assay 2: Colorimetric confirmation (IC50)(AID1059)IC50 value determined using sigmoidal dose response equationFloatμM
5Assay 3: (Qualifier)This qualifier is to be used with the next TID, IC50. If the qualifier is "=", the IC50 result equals the value in that column; if the qualifier is ">", the IC50 result is greater than that valueString
6Assay 3: VHR1 counterscreen (IC50)(AID1957)Assay 3: VHR1 counterscreen (IC50)(AID1957)FloatμM
7Assay 4: (Qualifier)This qualifier is to be used with the next TID, IC50. If the qualifier is "=", the IC50 result equals the value in that column; if the qualifier is ">", the IC50 result is greater than that valueString
8Assay 4: MKP-3 Counterscreen (IC50)(AID1055)FloatμM
9ML#ML# for the compoundString
Additional Information
Grant Number: XO1 MH077603-01

Data Table (Concise)
Data Table ( Complete ):     View Active Data    View All Data
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