Top ▲

CFTR

Click here for help

Target id: 707

Nomenclature: CFTR

Family: CFTR

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 12 1480 7q31.2 CFTR CF transmembrane conductance regulator
Mouse 12 1476 6 8.1 cM Cftr cystic fibrosis transmembrane conductance regulator
Rat 12 1476 4q21 Cftr CF transmembrane conductance regulator
Previous and Unofficial Names Click here for help
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 Click here for help
Alphafold P13569 (Hs), P26361 (Mm), P34158 (Rn)
ChEMBL Target CHEMBL4051 (Hs), CHEMBL3992 (Rn)
DrugBank Target P13569 (Hs)
Ensembl Gene ENSG00000001626 (Hs), ENSMUSG00000041301 (Mm), ENSRNOG00000055103 (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 Click here for help
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 go icon to follow link

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 Small molecule or natural product Approved drug Hs Potentiation 8.4 pKi - no 9
⤷ pKi 8.4 (Ki 4x10-9 M) [9]
Not voltage dependent
compound 16d [PMID: 36573286] Small molecule or natural product Hs Activation 7.6 pEC50 - no 7
⤷ pEC50 7.6 (EC50 2.3x10-8 M) [7]
Not voltage dependent
GLPG2737 Small molecule or natural product Hs - 6.2 – 7.2 pEC50 - no 11
⤷ pEC50 7.2 (EC50 7.1x10-8 M) Co-corrector [11]
Not voltage dependent
Description: In the presence of potentiator GLPG1837 and corrector GLPG2222- determined in a Transepithelial Clamp Circuit (TECC) electrophysiological assay
pEC50 6.2 (EC50 6.95x10-7 M) Co-corrector [11]
Not voltage dependent
Description: Determined in a Cell Surface Expression Horseradish Peroxidase (CSE-HRP) assay
capsaicin Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Potentiation - - - no
⤷
Not voltage dependent
nimodipine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Potentiation - - - no
⤷
Not voltage dependent
genistein Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Potentiation - - - no
⤷
Not voltage dependent
apigenin Small molecule or natural product Ligand has a PDB structure Hs Potentiation - - - no
⤷
Not voltage dependent
CBIQ Small molecule or natural product Hs Potentiation - - - no
⤷
Not voltage dependent
NS004 Small molecule or natural product Click here for species-specific activity table Hs Potentiation - - - no
⤷
Not voltage dependent
phenylglycine-01 Small molecule or natural product Hs Potentiation - - - no
⤷
Not voltage dependent
sulfonamide-01 Small molecule or natural product Hs Potentiation - - - no
⤷
Not voltage dependent
UCCF-029 Small molecule or natural product Hs Potentiation - - - no
⤷
Not voltage dependent
UCCF-339 Small molecule or natural product Hs Potentiation - - - no
⤷
Not voltage dependent
UCCF-853 Small molecule or natural product Hs Potentiation - - - no
⤷
Not voltage dependent
ivacaftor Small molecule or natural product Approved drug Ligand has a PDB structure Hs Potentiation - - - no 8
⤷ [8]
Not voltage dependent

Not voltage dependent
ABBV-3221 Small molecule or natural product Hs Potentiation - - - no 8,13
⤷ A CFTR corrector compound that increases protein levels at the cell surface. [8,13]
Not voltage dependent
GLPG1837 Small molecule or natural product Ligand has a PDB structure Hs Potentiation - - - no 4
⤷ [4]
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 Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Inhibition 5.2 pIC50 - no 15
⤷ pIC50 5.2 (IC50 7x10-6 M) [15]
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 Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs - 4.7 pKi - no 14
⤷ pKi 4.7 (Ki 2.18x10-5 M) [14]
Not voltage dependent
intracellular CFTRinh-172 Small molecule or natural product Hs - - - - no
⤷ intracellular application prolongs mean closed time
Not voltage dependent
GaTx1 Peptide Hs - - - - no
⤷
Not voltage dependent
extracellular GlyH-101 Small molecule or natural product Hs - - - - no
⤷
Not voltage dependent
Channel Blocker Comments
Malonic acid hydrazide conjugates are also CFTR channel blockers (see Verkman and Galietta, 2009 [16]).
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
bamocaftor Small molecule or natural product Hs Binding 7.5 pEC50 2-3
⤷ pEC50 7.5 (EC50 3x10-8 M) [2-3]
icenticaftor Small molecule or natural product Hs Potentiation 7.3 pEC50 5
⤷ pEC50 7.3 (EC50 4.7x10-8 M) [5]
Description: Current determined in CHO cells stably expressing the delF508-CFTR channel.
elexacaftor Small molecule or natural product Approved drug Ligand has a PDB structure Hs Binding 7.2 pEC50 1,6
⤷ pEC50 7.2 (EC50 7x10-8 M) [1,6]
tezacaftor Small molecule or natural product Approved drug Ligand has a PDB structure Hs Binding 6.6 pEC50 12
⤷ pEC50 6.6 (EC50 2.72x10-7 M) [12]
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 Small molecule or natural product Approved drug Ligand has a PDB structure Hs Binding 5.6 pEC50 10
⤷ pEC50 5.6 (EC50 2.6x10-6 M) [10]
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.
Immuno Process Associations
Immuno Process:  Immune regulation
Immuno Process:  Cellular signalling
Immuno Process:  Cytokine production & signalling
Immuno Process:  Inflammation
Clinically-Relevant Mutations and Pathophysiology Click here for help
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

Show »

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. Davies JC, Van de Steen O, van Koningsbruggen-Rietschel S, Drevinek P, Derichs N, McKone EF, Kanters D, Allamassey L, Namour F, de Kock H et al.. (2019) GLPG1837, a CFTR potentiator, in p.Gly551Asp (G551D)-CF patients: An open-label, single-arm, phase 2a study (SAPHIRA1). J Cyst Fibros, 18 (5): 693-699. [PMID:31147302]

5. Grand DL, Gosling M, Baettig U, Bahra P, Bala K, Brocklehurst C, Budd E, Butler R, Cheung AK, Choudhury H et al.. (2021) Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease. J Med Chem, 64 (11): 7241-7260. [PMID:34028270]

6. 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]

7. Kim BY, Oh C, Jeon D, Jun I, Lee HK, Kim BR, Park J, Seo KY, Kim KA, Lim D et al.. (2023) Synthetic Strategies for Improving Solubility: Optimization of Novel Pyrazolo[1,5-a]pyrimidine CFTR Activator That Ameliorates Dry Eye Disease. J Med Chem, 66 (1): 413-434. [PMID:36573286]

8. Levring J, Terry DS, Kilic Z, Fitzgerald G, Blanchard SC, Chen J. (2023) CFTR function, pathology and pharmacology at single-molecule resolution. Nature, 616 (7957): 606-614. [PMID:36949202]

9. 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]

10. 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]

11. Pizzonero M, Akkari R, Bock X, Gosmini R, De Lemos E, Duthion B, Newsome G, Mai TT, Roques V, Jary H et al.. (2024) Discovery of GLPG2737, a Potent Type 2 Corrector of CFTR for the Treatment of Cystic Fibrosis in Combination with a Potentiator and a Type 1 Co-corrector. J Med Chem, [Epub ahead of print]. [PMID:38527911]

12. 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.

13. 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]

14. 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]

15. 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]

16. 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 26/03/2024. Accessed on 15/10/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=707.