1. University College London, UK

Abstract

CFTR is a member of the ABC transporter superfamily, but, uniquely, it is an ion channel, allowing electrodiffusion of Cl^- and HCO3^-. It is activated by phosphorylation, mainly by PKA on its regulatory domain (R domain). Conserved nucleotide binding domains (NBD1 and NBD2) couple ATP binding and hydrolysis to gate opening and closing, respectively [8]. CFTR is expressed apically in polarized epithelial cells in various organs where it controls volume and pH of fluid secretions as well as mucin unfolding and release [26]. CFTR transcripts are present in secretory and ionocyte cells in airway epithelia [29, 33], crypt enterocytes, goblet and CFTR-high expressing cells in the intestine [5, 3], pancreatic duct cells [13], intra- and extra-hepatic cholangiocytes 33318612 [48] and others.
Mutations in the CFTR gene cause the genetic disease cystic fibrosis (CF) [38]. The most common mutation, F508del, is present in at least one gene copy in ~80% of patients worldwide, but there are ~1000 different variants known to cause CF. Mutations affect CFTR biogenesis (folding, maturation, trafficking, metabolic stability) and/or ion-channel function. Vertex Pharmaceuticals developed small-molecule CFTR modulator drugs that improve biogenesis ("correctors") or open probability ("potentiators") of defective CFTR variants. Triple combination therapies, including two correctors and one potentiator (e.g. Trikafta®: elexacaftor, tezacaftor, ivacaftor), are standard of care for patients carrying at least one copy of the F508del variant. Patients carrying mutations only affecting ion-channel function ("gating mutations" e.g. G551D) are treated with ivacaftor (potentiator) alone. Cryo-EM structures of Trikafta-bound F508del-E1371Q-CFTR reveal that all three compounds bind at the protein-membrane interface, in shallow pockets on CFTR's surface [14].
While low/absent CFTR activity causes CF, over-activation of CFTR (due to bacterial toxins such as cholera toxin) results in secretory diarrhoeas, causing large intestinal loss of fluid and alkali [11]. No inhibitors have been approved yet for emergency treatment of secretory diarrhoeas.

Contents

GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts. For further details see [4].

Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.

Database links

References

1. Abela AR, Alcacio T, Anderson C, Angell PT, Baek M, Clemens JJ, Cleveland T, Ferris LA, Grootenhuis PDJ and 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 and 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. Beumer J and Clevers H. (2021) Cell fate specification and differentiation in the adult mammalian intestine. Nat Rev Mol Cell Biol 22: 39-53 [PMID:32958874]
4. Buneman P, Christie G, Davies JA, Dimitrellou R, Harding SD, Pawson AJ, Sharman JL and Wu Y. (2020) Why data citation isn't working, and what to do about it Database 2020 [PMID:32367113]
5. Carlos Dos Reis D, Dastoor P, Santos AK, Sumigray K and Ameen NA. (2023) CFTR High Expresser Cells in cystic fibrosis and intestinal diseases. Heliyon 9: e14568 [PMID:36967909]
6. Chappe V, Hinkson DA, Zhu T, Chang XB, Riordan JR and Hanrahan JW. (2003) Phosphorylation of protein kinase C sites in NBD1 and the R domain control CFTR channel activation by PKA. J Physiol 548: 39-52 [PMID:12588899]
7. Csanády L and Töröcsik B. (2019) Cystic fibrosis drug ivacaftor stimulates CFTR channels at picomolar concentrations. Elife 8 [PMID:31205003]
8. Csanády L, Vergani P and Gadsby DC. (2019) STRUCTURE, GATING, AND REGULATION OF THE CFTR ANION CHANNEL. Physiol Rev 99: 707-738 [PMID:30516439]
9. Csanády L, Vergani P and Gadsby DC. (2010) Strict coupling between CFTR's catalytic cycle and gating of its Cl- ion pore revealed by distributions of open channel burst durations. Proc Natl Acad Sci U S A 107: 1241-6 [PMID:19966305]
10. Davies JC, Moskowitz SM, Brown C, Horsley A, Mall MA, McKone EF, Plant BJ, Prais D, Ramsey BW and 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: 1599-1611 [PMID:30334693]
11. de Jonge HR, Ardelean MC, Bijvelds MJC and Vergani P. (2020) Strategies for cystic fibrosis transmembrane conductance regulator inhibition: from molecular mechanisms to treatment for secretory diarrhoeas. FEBS Lett 594: 4085-4108 [PMID:33113586]
12. Evans IA, Sun X, Liang B, Vegter AR, Guo L, Lynch TJ, Zhang Y, Zhang Y, Yi Y and Yang Y et al.. (2024) In utero and postnatal ivacaftor/lumacaftor therapy rescues multiorgan disease in CFTR-F508del ferrets. JCI Insight 9 [PMID:38646935]
13. Fernández Á, Casamitjana J, Holguín-Horcajo A, Coolens K, Mularoni L, Guo L, Hartwig O, Düking T, Vidal N and Strickland LN et al.. (2024) A Single-Cell Atlas of the Murine Pancreatic Ductal Tree Identifies Novel Cell Populations With Potential Implications in Pancreas Regeneration and Exocrine Pathogenesis. Gastroenterology 167: 944-960.e15 [PMID:38908487]
14. Fiedorczuk K and Chen J. (2022) Molecular structures reveal synergistic rescue of Δ508 CFTR by Trikafta modulators. Science 378: 284-290 [PMID:36264792]
15. Fuller MD, Thompson CH, Zhang ZR, Freeman CS, Schay E, Szakács G, Bakos E, Sarkadi B, McMaster D and French RJ et al.. (2007) State-dependent inhibition of cystic fibrosis transmembrane conductance regulator chloride channels by a novel peptide toxin. J Biol Chem 282: 37545-55 [PMID:17951250]
16. Gao X, Yeh HI, Yang Z, Fan C, Jiang F, Howard RJ, Lindahl E, Kappes JC and Hwang TC. (2024) Allosteric inhibition of CFTR gating by CFTRinh-172 binding in the pore. Nat Commun 15: 6668 [PMID:39107303]
17. Grand DL, Gosling M, Baettig U, Bahra P, Bala K, Brocklehurst C, Budd E, Butler R, Cheung AK and 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: 7241-7260 [PMID:34028270]
18. Guilbault C, Saeed Z, Downey GP and Radzioch D. (2007) Cystic fibrosis mouse models. Am J Respir Cell Mol Biol 36: 1-7 [PMID:16888286]
19. Hadida S, Van Goor F, Zhou J, Arumugam V, McCartney J, Hazlewood A, Decker C, Negulescu P and Grootenhuis PD. (2014) Discovery of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, ivacaftor), a potent and orally bioavailable CFTR potentiator. J Med Chem 57: 9776-95 [PMID:25441013]
20. Harbeson SL, Morgan AJ, Liu JF, Aslanian AM, Nguyen S, Bridson GW, Brummel CL, Wu L, Tung RD and Pilja L et al.. (2017) Altering Metabolic Profiles of Drugs by Precision Deuteration 2: Discovery of a Deuterated Analog of Ivacaftor with Differentiated Pharmacokinetics for Clinical Development. J Pharmacol Exp Ther 362: 359-367 [PMID:28611092]
21. Keating C, Yonker LM, Vermeulen F, Prais D, Linnemann RW, Trimble A, Kotsimbos T, Mermis J, Braun AT and O'Carroll M et al.. (2025) Vanzacaftor-tezacaftor-deutivacaftor versus elexacaftor-tezacaftor-ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): results from two randomised, active-controlled, phase 3 trials. Lancet Respir Med 13: 256-271 [PMID:39756424]
22. Keating D, Marigowda G, Burr L, Daines C, Mall MA, McKone EF, Ramsey BW, Rowe SM, Sass LA and 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: 1612-1620 [PMID:30334692]
23. Kim BY, Oh C, Jeon D, Jun I, Lee HK, Kim BR, Park J, Seo KY, Kim KA and 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: 413-434 [PMID:36573286]
24. Levring J, Terry DS, Kilic Z, Fitzgerald G, Blanchard SC and Chen J. (2023) CFTR function, pathology and pharmacology at single-molecule resolution. Nature 616: 606-614 [PMID:36949202]
25. Linsdell P. (2017) Architecture and functional properties of the CFTR channel pore. Cell Mol Life Sci 74: 67-83 [PMID:27699452]
26. Mall MA, Burgel PR, Castellani C, Davies JC, Salathe M and Taylor-Cousar JL. (2024) Cystic fibrosis. Nat Rev Dis Primers 10: 53 [PMID:39117676]
27. Mihályi C, Iordanov I, Szollosi A and Csanády L. (2024) Structural determinants of protein kinase A essential for CFTR channel activation. Proc Natl Acad Sci U S A 121: e2407728121 [PMID:39495914]
28. Muanprasat C, Sonawane ND, Salinas D, Taddei A, Galietta LJ and Verkman AS. (2004) Discovery of glycine hydrazide pore-occluding CFTR inhibitors: mechanism, structure-activity analysis, and in vivo efficacy. J Gen Physiol 124: 125-37 [PMID:15277574]
29. Okuda K, Dang H, Kobayashi Y, Carraro G, Nakano S, Chen G, Kato T, Asakura T, Gilmore RC and Morton LC et al.. (2021) Secretory Cells Dominate Airway CFTR Expression and Function in Human Airway Superficial Epithelia. Am J Respir Crit Care Med 203: 1275-1289 [PMID:33321047]
30. Pedemonte N, Boido D, Moran O, Giampieri M, Mazzei M, Ravazzolo R and Galietta LJ. (2007) Structure-activity relationship of 1,4-dihydropyridines as potentiators of the cystic fibrosis transmembrane conductance regulator chloride channel. Mol Pharmacol 72: 197-207 [PMID:17452495]
31. Pesci E, Bettinetti L, Fanti P, Galietta LJ, La Rosa S, Magnoni L, Pedemonte N, Sardone GL and 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: 9697-711 [PMID:26561003]
32. Pizzonero M, Akkari R, Bock X, Gosmini R, De Lemos E, Duthion B, Newsome G, Mai TT, Roques V and 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 67: 5216-5232 [PMID:38527911]
33. Plasschaert LW, Žilionis R, Choo-Wing R, Savova V, Knehr J, Roma G, Klein AM and Jaffe AB. (2018) A single-cell atlas of the airway epithelium reveals the CFTR-rich pulmonary ionocyte. Nature 560: 377-381 [PMID:30069046]
34. Ruah SSH, Grootenhuis PDJ, Van Goor F, Zhou J, Bear B, Miller MT, McCartney J and 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.
35. Scanio MJC, Searle XB, Liu B, Koenig JR, Altenbach R, Gfesser GA, Bogdan A, Greszler S, Zhao G and 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: 1543-1548 [PMID:31749908]
36. Seidler U, Blumenstein I, Kretz A, Viellard-Baron D, Rossmann H, Colledge WH, Evans M, Ratcliff R and Gregor M. (1997) A functional CFTR protein is required for mouse intestinal cAMP-, cGMP- and Ca(2+)-dependent HCO3- secretion. J Physiol 505 ( Pt 2): 411-23 [PMID:9423183]
37. Sheppard DN and Welsh MJ. (1992) Effect of ATP-sensitive K+ channel regulators on cystic fibrosis transmembrane conductance regulator chloride currents. J Gen Physiol 100: 573-91 [PMID:1281220]
38. Shteinberg M, Haq IJ, Polineni D and Davies JC. (2021) Cystic fibrosis. Lancet 397: 2195-2211 [PMID:34090606]
39. Snyder DS, Tradtrantip L, Battula S, Yao C, Phuan PW, Fettinger JC, Kurth MJ and Verkman AS. (2013) ABSOLUTE CONFIGURATION AND BIOLOGICAL PROPERTIES OF ENANTIOMERS OF CFTR INHIBITOR BPO-27. ACS Med Chem Lett 4: 456-459 [PMID:23814642]
40. Stewart CG, Hilkin BM, Gansemer ND, Adam RJ, Dick DW, Sunderland JJ, Stoltz DA, Zabner J and Abou Alaiwa MH. (2024) Mucociliary clearance is impaired in small airways of cystic fibrosis pigs. Am J Physiol Lung Cell Mol Physiol 327: L415-L422 [PMID:39104314]
41. Stoltz DA, Meyerholz DK, Pezzulo AA, Ramachandran S, Rogan MP, Davis GJ, Hanfland RA, Wohlford-Lenane C, Dohrn CL and Bartlett JA et al.. (2010) Cystic fibrosis pigs develop lung disease and exhibit defective bacterial eradication at birth. Sci Transl Med 2: 29ra31 [PMID:20427821]
42. Sun X, Yi Y, Yan Z, Rosen BH, Liang B, Winter MC, Evans TIA, Rotti PG, Yang Y and Gray JS et al.. (2019) In utero and postnatal VX-770 administration rescues multiorgan disease in a ferret model of cystic fibrosis. Sci Transl Med 11 [PMID:30918114]
43. Tan Q, di Stefano G, Tan X, Renjie X, Römermann D, Talbot SR and Seidler UE. (2021) Inhibition of Na⁺ /H⁺ exchanger isoform 3 improves gut fluidity and alkalinity in cystic fibrosis transmembrane conductance regulator-deficient and F508del mutant mice. Br J Pharmacol 178: 1018-1036 [PMID:33179259]
44. Tradtrantip L, Namkung W and Verkman AS. (2010) Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels. Mol Pharmacol 77: 69-78 [PMID:19808995]
45. Vaandrager AB, Bot AG and De Jonge HR. (1997) Guanosine 3',5'-cyclic monophosphate-dependent protein kinase II mediates heat-stable enterotoxin-provoked chloride secretion in rat intestine. Gastroenterology 112: 437-43 [PMID:9024297]
46. Vergani P, Lockless SW, Nairn AC and Gadsby DC. (2005) CFTR channel opening by ATP-driven tight dimerization of its nucleotide-binding domains. Nature 433: 876-80 [PMID:15729345]
47. Verkman AS and Galietta LJ. (2009) Chloride channels as drug targets. Nat Rev Drug Discov 8: 153-71 [PMID:19153558]
48. Verstegen MMA, Roos FJM, Burka K, Gehart H, Jager M, de Wolf M, Bijvelds MJC, de Jonge HR, Ardisasmita AI and van Huizen NA et al.. (2020) Human extrahepatic and intrahepatic cholangiocyte organoids show region-specific differentiation potential and model cystic fibrosis-related bile duct disease. Sci Rep 10: 21900 [PMID:33318612]
49. Yeh HI, Sohma Y, Conrath K and Hwang TC. (2017) A common mechanism for CFTR potentiators. J Gen Physiol 149: 1105-1118 [PMID:29079713]