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BioAssay: AID 1574

Summary assay for the identification of compounds that inhibit PHOSPHO1

Mineralization of cartilage and bone occurs by a series of physicochemical and biochemical processes that together facilitate the deposition of hydroxyapatite (HA) in specific areas of the extracellular matrix (ECM). Experimental evidence has pointed to the presence of HA crystals along collagen fibrils in the ECM and also within the lumen of chondroblast- and osteoblast-derived matrix vesicles more ..
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 Tested Compounds
 Tested Compounds
All(1)
 
 
Probe(1)
 
 
Active(1)
 
 
 Tested Substances
 Tested Substances
All(1)
 
 
Probe(1)
 
 
Active(1)
 
 
AID: 1574
Data Source: Burnham Center for Chemical Genomics (BCCG-A155-Phospho1-Summary-Assay)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2009-03-23
Modify Date: 2010-12-30

Data Table ( Complete ):           View Active Data    View All Data
Target
BioActive Compound: Chemical Probe: 1    Active: 1
Related Experiments
AIDNameTypeComment
1056SAR analysis of an In Vitro TNAP Dose Response Luminescent AssayConfirmatorydepositor-specified cross reference: Anti-target in Vitro TNAP Dose Response Luminescent Assay for SAR Study
1535Confirmation of compounds inhibiting phosphomannose isomerase (PMI) via a fluorescence intensity assay.Confirmatorydepositor-specified cross reference: Confirmation of compounds inhibiting phosphomannoseisomerase (PMI) via a fluorescence intensity assa
1565uHTS absorbance assay for the identification of compounds that inhibit PHOSPHO1Confirmatorydepositor-specified cross reference: uHTS absorbance assay for the identification of compounds that inhibit PHOSPHO1.
1655Counter screen SAR assay for PMM2 inhibitors via a fluorescence intensity assayConfirmatorydepositor-specified cross reference: Counter screen SAR assay for PMM2 inhibitors via a fluorescence intensity assay
1666SAR assay for compounds that inhibit PHOSPHO1Confirmatorydepositor-specified cross reference: SAR assay for compounds that inhibit PHOSPHO1
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: 1 R03 MH084086-01
Assay Provider: Dr. Jose Luis Milan, Sanford-Burnham Medical Research Institute, San Diego CA

Mineralization of cartilage and bone occurs by a series of physicochemical and biochemical processes that together facilitate the deposition of hydroxyapatite (HA) in specific areas of the extracellular matrix (ECM). Experimental evidence has pointed to the presence of HA crystals along collagen fibrils in the ECM and also within the lumen of chondroblast- and osteoblast-derived matrix vesicles (MVs). Dr. Milan's working model is that bone mineralization is first initiated within the lumen of MVs. In a second step, HA crystals grow beyond the confines of the MVs and become exposed to the extracellular milieu where they continue to propagate along collagen fibrils. Recent data have indicated that tissue-nonspecific alkaline phosphatase (TNAP) plays a crucial role in restricting the concentration of extracellular inorganic pyrophosphate (PP), a mineralization inhibitor, to maintain a P/PPi ratio permissive for normal bone mineralization. Using a variety of single and double gene knockout experiments it has been found that mice deficient in TNAP function, i.e., Akp2-/- mice, display osteomalacia due to an arrest in the propagation of HA crystals outside the MVs caused by an increase in extracellular PPi concentrations. Inside the MVs, however, HA crystals are still present in Akp2-/- mice. It is hypothesize that a newly identified soluble phosphatase, PHOSPHO1, with specificity for phosphoethanolamine (PEA) and phosphoserine (PS) present in the MVs, is responsible for increasing the local concentration of Pi inside the MVs to change the P/PPi ratio to favor precipitation of HA seed crystals.

This AID summarizes the biological properties of the probe molecule, SID-57287582(ML086) characterized by a battery of secondary and counter assays(1056, 1535, 1565, 1655, 1666).
Protocol
See pertinent assays: 1056, 1535, 1565, 1655, 1666
Comment
Probe molecules are defined as the positives of this assay and assigned a score of 100
Categorized Comment - additional comments and annotations
From MLP Probe Report:
Probe count: 1
MLP Probe ML# for probe 1: ML086
PubChem Substance ID (SID) for probe 1: 57287582
PubChem Compound ID (CID) for probe 1: 16749996
Probe type for probe 1: Inhibitor
IC50/EC50 (nM) for probe 1: 139
Target for probe 1: PHOSPHO-1 (gi: 219689097)
Anti-target for probe 1: TNAP
Fold selectivity for probe 1: >719
NCBI Book chapter link for probe 1: http://www.ncbi.nlm.nih.gov/books/NBK47355/ (ID: 2359738)
Grant number for probe 1: MH084086-01
NCBI Book chapter title for probe 1: The Role of PHOSPHO1 in the Initiation of Skeletal Calcification
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1ML#ML# for the compoundString
Additional Information
Grant Number: 1 R03 MH084086-01

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