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BioAssay: AID 501164

Inhibition of human CFTR expressed in forskolin and IBMX-stimulated rat FRT cells assessed as reduction in channel open probability at 1 uM by cell-attached single channel patch clamp assay

Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are predicted to slow cyst enlargement in polycystic kidney disease and reduce intestinal fluid loss in secretory diarrheas. Screening of approximately 110000 small synthetic and natural compounds for inhibition of halide influx in CFTR-expressing epithelial cells yielded a new class of more ..
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 Tested Compounds
 Tested Compounds
All(1)
 
 
Active(1)
 
 
 Tested Substances
 Tested Substances
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Active(1)
 
 
 Related BioAssays
 Related BioAssays
AID: 501164
Data Source: ChEMBL (651204)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2011-02-25
Modify Date: 2013-11-16

Data Table ( Complete ):           Active    All
Target
Sequence: RecName: Full=Cystic fibrosis transmembrane conductance regulator; Short=CFTR; AltName: Full=ATP-binding cassette sub-family C member 7; AltName: Full=Channel conductance-controlling ATPase; AltName: Full=cAMP-dependent chloride channel
Description ..   
Protein Family: ATP-binding cassette domain of the cystic fibrosis transmembrane regulator, subfamily C
Comment ..   

Gene:CFTR     Related Protein 3D Structures     More BioActivity Data..
BioActive Compound: 1
Description:
Title: Nanomolar potency pyrimido-pyrrolo-quinoxalinedione CFTR inhibitor reduces cyst size in a polycystic kidney disease model.

Abstract: Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are predicted to slow cyst enlargement in polycystic kidney disease and reduce intestinal fluid loss in secretory diarrheas. Screening of approximately 110000 small synthetic and natural compounds for inhibition of halide influx in CFTR-expressing epithelial cells yielded a new class of pyrimido-pyrrolo-quinoxalinedione (PPQ) CFTR inhibitors. Testing of 347 analogues established structure-activity relationships. The most potent compound, 7,9-dimethyl-11-phenyl-6-(5-methylfuran-2-yl)-5,6-dihydro-pyrimido[4',5'-3,4]pyrrolo[1,2-a]quinoxaline-8,10-(7H,9H)-dione, PPQ-102, completely inhibited CFTR chloride current with IC(50) approximately 90 nM. The PPQs, unlike prior CFTR inhibitors, are uncharged at physiological pH, and therefore not subject to membrane potential-dependent cellular partitioning or block efficiency. Patch-clamp analysis confirmed voltage-independent CFTR inhibition by PPQ-102 and showed stabilization of the channel closed state. PPQ-102 prevented cyst expansion and reduced the size of preformed cysts in a neonatal kidney organ culture model of polycystic kidney disease. PPQ-102 is the most potent CFTR inhibitor identified to date.
(PMID: 19785436)
Categorized Comment
ChEMBL Assay Type: Binding

ChEMBL Assay Data Source: Scientific Literature

ChEMBL Target ID: 11540

ChEMBL Target Type: Target is a single protein chain

Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1Activity activity commentActivity activity commentString
2Activity standard flagActivity standard flagInteger
3Activity qualifierActivity qualifierString
4Activity published valueActivity published valueFloat
5Activity standard valueActivity standard valueFloat

Data Table (Concise)
Classification
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