CFTR | CFTR | IUPHAR/BPS Guide to PHARMACOLOGY

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CFTR

Target not currently curated in GtoImmuPdb

Target id: 707

Nomenclature: CFTR

Family: CFTR

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Contents:

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1480 7q31-q32 CFTR CF transmembrane conductance regulator
Mouse - 1476 6 A3 Cftr cystic fibrosis transmembrane conductance regulator
Rat - 1476 4q21 Cftr CF transmembrane conductance regulator
Previous and Unofficial Names
ABCC7 | ABC35 | CFTR/MRP | MRP7 | TNR-CFTR | ATP-binding cassette sub-family C member 7 | cAMP-dependent chloride channel | cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)
Database Links
ChEMBL Target CHEMBL4051 (Hs), CHEMBL3992 (Rn)
DrugBank Target P13569 (Hs)
Ensembl Gene ENSG00000001626 (Hs), ENSMUSG00000041301 (Mm), ENSRNOG00000008284 (Rn)
Entrez Gene 1080 (Hs), 12638 (Mm), 24255 (Rn)
Human Protein Atlas ENSG00000001626 (Hs)
KEGG Gene hsa:1080 (Hs), mmu:12638 (Mm), rno:24255 (Rn)
OMIM 602421 (Hs)
Orphanet ORPHA119382 (Hs)
Pharos P13569 (Hs)
UniProtKB P13569 (Hs), P26361 (Mm), P34158 (Rn)
Wikipedia CFTR (Hs)
Functional Characteristics
γ = 6-10 pS; permeability sequence = Br- ≥ Cl- > I- > F-, (PI/PCl = 0.1–0.85); slight outward rectification; phosphorylation necessary for activation by ATP binding at binding nucleotide binding domains (NBD)1 and 2; positively regulated by PKC and PKGII (tissue specific); regulated by several interacting proteins including syntaxin 1A, Munc18 and PDZ domain proteins such as NHERF (EBP50) and CAP70

Download all structure-activity data for this target as a CSV file

Activators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
felodipine Hs Potentiation 8.4 pKi - no 5
⤷ pKi 8.4 (Ki 4x10-9 M) [5]
Not voltage dependent
capsaicin Hs Potentiation - - - no
⤷
Not voltage dependent
nimodipine Hs Potentiation - - - no
⤷
Not voltage dependent
genistein Hs Potentiation - - - no
⤷
Not voltage dependent
apigenin Hs Potentiation - - - no
⤷
Not voltage dependent
CBIQ Hs Potentiation - - - no
⤷
Not voltage dependent
NS004 Hs Potentiation - - - no
⤷
Not voltage dependent
phenylglycine-01 Hs Potentiation - - - no
⤷
Not voltage dependent
sulfonamide-01 Hs Potentiation - - - no
⤷
Not voltage dependent
UCCF-029 Hs Potentiation - - - no
⤷
Not voltage dependent
UCCF-339 Hs Potentiation - - - no
⤷
Not voltage dependent
UCCF-853 Hs Potentiation - - - no
⤷
Not voltage dependent
ivacaftor Hs Potentiation - - - no
⤷
Not voltage dependent
Activator Comments
UCCF-339, UCCF-029, apigenin and genistein are examples of flavones. UCCF-853 and NS004 are examples of benzimidazolones. CBIQ is an example of a benzoquinoline. felodipine and nimodipine are examples of 1,4-dihydropyridines. Phenylglycine-01 is an example of a phenylglycine. SF-01 is an example of a sulfonamide.
Inhibitors
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
crofelemer Hs Inhibition 5.2 pIC50 - no 10
⤷ pIC50 5.2 (IC50 7x10-6 M) [10]
Not voltage dependent
Channel Blockers
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Concentration range (M) Voltage-dependent (mV) Reference
glibenclamide Hs - 4.7 pKi - no 9
⤷ pKi 4.7 (Ki 2.18x10-5 M) [9]
Not voltage dependent
intracellular CFTRinh-172 Hs - - - - no
⤷ intracellular application prolongs mean closed time
Not voltage dependent
GaTx1 Hs - - - - no
⤷
Not voltage dependent
extracellular GlyH-101 Hs - - - - no
⤷
Not voltage dependent
Channel Blocker Comments
Malonic acid hydrazide conjugates are also CFTR channel blockers (see Verkman and Galietta, 2009 [11]).
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
bamocaftor Hs Binding 7.5 pEC50 2-3
⤷ pEC50 7.5 (EC50 3x10-8 M) [2-3]
elexacaftor Hs Binding 7.2 pEC50 1,4
⤷ pEC50 7.2 (EC50 7x10-8 M) [1,4]
tezacaftor Hs Binding 6.6 pEC50 7
⤷ pEC50 6.6 (EC50 2.72x10-7 M) [7]
Description: Measuring the increase in cAMP/genistein-dependent current amplitude via the ΔF508-CFTR mutant expressed in NIH/3T3 cells by patch-clamp recording, in response to tezacaftor exposure.
lumacaftor Hs Binding 5.6 pEC50 6
⤷ pEC50 5.6 (EC50 2.6x10-6 M) [6]
Description: EC50 determined by measuring F508del-CFTR (expressed in FRT cells) activity (I– influx; wih co-expression of a fluorescent YFP halide sensor) in the presence of increasing doses of test compound.
ABBV-3221 Hs Binding - - 8
⤷ A CFTR corrector compound that increases protein levels at the cell surface. [8]
Immuno Process Associations
Immuno Process:  Immune regulation
GO Annotations:  Associated to 1 GO processes
GO:0033005 positive regulation of mast cell activation ISO
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes
GO:0033005 positive regulation of mast cell activation ISO
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 1 GO processes
GO:0034097 response to cytokine IEP
Immuno Process:  Inflammation
GO Annotations:  Associated to 1 GO processes
GO:0033005 positive regulation of mast cell activation ISO
Clinically-Relevant Mutations and Pathophysiology
Disease:  Bronchiectasis with or without elevated sweat chloride 1, BESC1
Synonyms: Bronchiectasis [Disease Ontology: DOID:9563]
Idiopathic bronchiectasis [Orphanet: ORPHA60033]
Disease Ontology: DOID:9563
OMIM: 211400
Orphanet: ORPHA60033
Disease:  Congenital bilateral absence of vas deferens
OMIM: 277180
Orphanet: ORPHA48
Disease:  Cystic fibrosis
Disease Ontology: DOID:1485
OMIM: 219700
Orphanet: ORPHA586
Disease:  Hereditary pancreatitis
Synonyms: Hereditary chronic pancreatitis [Orphanet: ORPHA676]
OMIM: 167800
Orphanet: ORPHA676
Disease:  Male infertility with normal virilization due to meiosis defect
Orphanet: ORPHA217034

References

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1. Abela AR, Alcacio T, Anderson C, Angell PT, Baek M, Clemens JJ, Cleveland T, Ferris LA, Grootenhuis PDJ, Gross RS et al.. (2018) Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator. Patent number: WO2018107100A1. Assignee: Vertex Pharmaceuticals. Priority date: 09/12/2016. Publication date: 14/04/2019.

2. Alcacio T, Baek M, Grootenhuis P, Hadida Ruah SS, Hughes RM, Keshavarz-Shokri A, McAuley-Aoki R, McCartney J, Miller MT, Van Goor F et al.. (2018) Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator. Patent number: WO2018064632A1. Assignee: Vertex Pharmaceuticals. Priority date: 30/09/2016. Publication date: 05/04/2018.

3. Davies JC, Moskowitz SM, Brown C, Horsley A, Mall MA, McKone EF, Plant BJ, Prais D, Ramsey BW, Taylor-Cousar JL et al.. (2018) VX-659-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N. Engl. J. Med., 379 (17): 1599-1611. [PMID:30334693]

4. Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, Ramsey BW, Rowe SM, Sass LA, Tullis E et al.. (2018) VX-445-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and One or Two Phe508del Alleles. N. Engl. J. Med., 379 (17): 1612-1620. [PMID:30334692]

5. Pedemonte N, Boido D, Moran O, Giampieri M, Mazzei M, Ravazzolo R, Galietta LJ. (2007) Structure-activity relationship of 1,4-dihydropyridines as potentiators of the cystic fibrosis transmembrane conductance regulator chloride channel. Mol. Pharmacol., 72 (1): 197-207. [PMID:17452495]

6. Pesci E, Bettinetti L, Fanti P, Galietta LJ, La Rosa S, Magnoni L, Pedemonte N, Sardone GL, Maccari L. (2015) Novel Hits in the Correction of ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Protein: Synthesis, Pharmacological, and ADME Evaluation of Tetrahydropyrido[4,3-d]pyrimidines for the Potential Treatment of Cystic Fibrosis. J. Med. Chem., 58 (24): 9697-711. [PMID:26561003]

7. Ruah SSH, Grootenhuis PDJ, Van Goor F, Zhou J, Bear B, Miller MT, McCartney J, Numa MMD. (2009) Indole derivatives as CFTR modulators. Patent number: US20090131492A1. Assignee: ertex Pharmaceuticals Inc. Priority date: 07/04/2006. Publication date: 21/05/2009.

8. Scanio MJC, Searle XB, Liu B, Koenig JR, Altenbach R, Gfesser GA, Bogdan A, Greszler S, Zhao G, Singh A et al.. (2019) Discovery of ABBV/GLPG-3221, a Potent Corrector of CFTR for the Treatment of Cystic Fibrosis. ACS Med Chem Lett, 10 (11): 1543-1548. [PMID:31749908]

9. Sheppard DN, Welsh MJ. (1992) Effect of ATP-sensitive K+ channel regulators on cystic fibrosis transmembrane conductance regulator chloride currents. J. Gen. Physiol., 100 (4): 573-91. [PMID:1281220]

10. Tradtrantip L, Namkung W, Verkman AS. (2010) Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels. Mol. Pharmacol., 77 (1): 69-78. [PMID:19808995]

11. Verkman AS, Galietta LJ. (2009) Chloride channels as drug targets. Nat Rev Drug Discov, 8 (2): 153-71. [PMID:19153558]

How to cite this page

CFTR: CFTR. Last modified on 06/12/2019. Accessed on 29/05/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=707.