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BioAssay: AID 255091

Inhibitory concentration against wild type mutant human thioredoxin reductase (hTrxRdelta-16) pre-incubated for 10 min at 25 degree C in buffer in the presence of 200 uM NADPH

The human selenoprotein thioredoxin reductase is involved in antioxidant defense and DNA synthesis. As increased thioredoxin reductase levels are associated with drug sensitivity to cisplatin and drug resistance in tumor cells, this enzyme represents a promising target for the development of cytostatic agents. To optimize the potential of the widely used cisplatin to inhibit the human thioredoxin more ..
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 Tested Compounds
 Tested Compounds
All(1)
 
 
Active(1)
 
 
 Tested Substances
 Tested Substances
All(2)
 
 
Active(2)
 
 
AID: 255091
Data Source: ChEMBL (321567)
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2010-05-24
Modify Date: 2014-08-24

Data Table ( Complete ):           View Active Data    View All Data
Targets
Sequence: RecName: Full=Thioredoxin reductase 1, cytoplasmic; Short=TR; AltName: Full=Gene associated with retinoic and interferon-induced mortality 12 protein; Short=GRIM-12; Short=Gene associated with retinoic and IFN-induced mortality 12 protein; AltName: Full=KM-102-derived reductase-like factor; AltName: Full=Thioredoxin reductase TR1
Description ..   
Protein Family: Pyridine nucleotide-disulphide oxidoreductase, dimerization domain
Comment ..   

Gene:TXNRD1     Related Protein 3D Structures     More BioActivity Data..


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BioActive Compound: 1
Description:
Title: Synthesis of 5-nitro-2-furancarbohydrazides and their cis-diamminedichloroplatinum complexes as bitopic and irreversible human thioredoxin reductase inhibitors.

Abstract: The human selenoprotein thioredoxin reductase is involved in antioxidant defense and DNA synthesis. As increased thioredoxin reductase levels are associated with drug sensitivity to cisplatin and drug resistance in tumor cells, this enzyme represents a promising target for the development of cytostatic agents. To optimize the potential of the widely used cisplatin to inhibit the human thioredoxin reductase and therefore to overcome cisplatin resistance, we developed and synthesized four cis-diamminedichloroplatinum complexes of the lead 5-nitro-2-furancarbohydrazide 8 selected from high-throughput screening. Detailed kinetics revealed that the isolated fragments, 5-nitro-2-furancarbohydrazide and cisplatin itself, bind with micromolar affinities at two different subsites of the human enzyme. By tethering both fragments four nitrofuran-based cis-diamminedichloroplatinum complexes 13a-c and 20 were synthesized and identified as bi-ligand irreversible inhibitors of the human enzyme with nanomolar affinities. Studies with mutant enzymes clearly demonstrate the penultimate selenocysteine residue as the prime target of the synthesized cis-diamminedichloroplatinum complexes.
(PMID: 16250662)
Comment
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.

Categorized Comment - additional comments and annotations
From BioAssay Depositor:
Assay Type: Binding
Target Type: Target is a group of closely related proteins
Assay Data Source: Scientific Literature
Protein Target Class: enzyme reductase
Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1IC50*IC50 PubChem standard valueFloatμM
3BEIBinding Efficiency Index(nM)Float
2SEISurface Efficiency Index(nM)Float
4LELigand EfficiencyFloat
5LLELipophilic Ligand EfficiencyFloat
6IC50 activity commentIC50 activity commentString
7IC50 standard flagIC50 standard flagInteger
8IC50 qualifierIC50 qualifierString
9IC50 published valueIC50 published valueFloatnM
10IC50 standard valueIC50 standard valueFloatnM

* Activity Concentration.

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