Target Information
| Target General Information | Top | |||||
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| Target ID |
T55654
(Former ID: TTDNS00605)
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| Target Name |
cAMP-dependent chloride channel (CFTR)
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| Synonyms |
cAMPdependent chloride channel; Cystic fibrosis transmembrane conductance regulator; Channel conductancecontrolling ATPase; ATPbinding cassette subfamily C member 7; ATP-binding cassette sub-family C member 7; ABCC7
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| Gene Name |
CFTR
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Cystic fibrosis [ICD-11: CA25] | |||||
| 2 | Intrathoracic organs injury [ICD-11: NB32] | |||||
| 3 | Viral intestinal infection [ICD-11: 1A2Z] | |||||
| Function |
Mediates the transport of chloride ions across the cell membrane. Channel activity is coupled to ATP hydrolysis. The ion channel is also permeable to HCO(3-); selectivity depends on the extracellular chloride concentration. Exerts its function also by modulating the activity of other ion channels and transporters. Plays an important role in airway fluid homeostasis. Contributes to the regulation of the pH and the ion content of the airway surface fluid layer and thereby plays an important role in defense against pathogens. Modulates the activity of the epithelial sodium channel (ENaC) complex, in part by regulating the cell surface expression of the ENaC complex. Inhibits the activity of the ENaC channel containing subunits SCNN1A, SCNN1B and SCNN1G. Inhibits the activity of the ENaC channel containing subunits SCNN1D, SCNN1B and SCNN1G, but not of the ENaC channel containing subunits SCNN1A, SCNN1B and SCNN1G. May regulate bicarbonate secretion and salvage in epithelial cells by regulating the transporter SLC4A7. Can inhibit the chloride channel activity of ANO1. Plays a role in the chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation. Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis.
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| BioChemical Class |
ABC transporter
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| UniProt ID | ||||||
| EC Number |
EC 5.6.1.6
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| Sequence |
MQRSPLEKASVVSKLFFSWTRPILRKGYRQRLELSDIYQIPSVDSADNLSEKLEREWDRE
LASKKNPKLINALRRCFFWRFMFYGIFLYLGEVTKAVQPLLLGRIIASYDPDNKEERSIA IYLGIGLCLLFIVRTLLLHPAIFGLHHIGMQMRIAMFSLIYKKTLKLSSRVLDKISIGQL VSLLSNNLNKFDEGLALAHFVWIAPLQVALLMGLIWELLQASAFCGLGFLIVLALFQAGL GRMMMKYRDQRAGKISERLVITSEMIENIQSVKAYCWEEAMEKMIENLRQTELKLTRKAA YVRYFNSSAFFFSGFFVVFLSVLPYALIKGIILRKIFTTISFCIVLRMAVTRQFPWAVQT WYDSLGAINKIQDFLQKQEYKTLEYNLTTTEVVMENVTAFWEEGFGELFEKAKQNNNNRK TSNGDDSLFFSNFSLLGTPVLKDINFKIERGQLLAVAGSTGAGKTSLLMVIMGELEPSEG KIKHSGRISFCSQFSWIMPGTIKENIIFGVSYDEYRYRSVIKACQLEEDISKFAEKDNIV LGEGGITLSGGQRARISLARAVYKDADLYLLDSPFGYLDVLTEKEIFESCVCKLMANKTR ILVTSKMEHLKKADKILILHEGSSYFYGTFSELQNLQPDFSSKLMGCDSFDQFSAERRNS ILTETLHRFSLEGDAPVSWTETKKQSFKQTGEFGEKRKNSILNPINSIRKFSIVQKTPLQ MNGIEEDSDEPLERRLSLVPDSEQGEAILPRISVISTGPTLQARRRQSVLNLMTHSVNQG QNIHRKTTASTRKVSLAPQANLTELDIYSRRLSQETGLEISEEINEEDLKECFFDDMESI PAVTTWNTYLRYITVHKSLIFVLIWCLVIFLAEVAASLVVLWLLGNTPLQDKGNSTHSRN NSYAVIITSTSSYYVFYIYVGVADTLLAMGFFRGLPLVHTLITVSKILHHKMLHSVLQAP MSTLNTLKAGGILNRFSKDIAILDDLLPLTIFDFIQLLLIVIGAIAVVAVLQPYIFVATV PVIVAFIMLRAYFLQTSQQLKQLESEGRSPIFTHLVTSLKGLWTLRAFGRQPYFETLFHK ALNLHTANWFLYLSTLRWFQMRIEMIFVIFFIAVTFISILTTGEGEGRVGIILTLAMNIM STLQWAVNSSIDVDSLMRSVSRVFKFIDMPTEGKPTKSTKPYKNGQLSKVMIIENSHVKK DDIWPSGGQMTVKDLTAKYTEGGNAILENISFSISPGQRVGLLGRTGSGKSTLLSAFLRL LNTEGEIQIDGVSWDSITLQQWRKAFGVIPQKVFIFSGTFRKNLDPYEQWSDQEIWKVAD EVGLRSVIEQFPGKLDFVLVDGGCVLSHGHKQLMCLARSVLSKAKILLLDEPSAHLDPVT YQIIRRTLKQAFADCTVILCEHRIEAMLECQQFLVIEENKVRQYDSIQKLLNERSLFRQA ISPSDRVKLFPHRNSSKCKSKPQIAALKEETEEEVQDTRL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T53KY7 | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 4 Approved Drugs | + | ||||
| 1 | Crofelemer | Drug Info | Approved | HIV-associated diarrhoea | [2], [3], [4] | |
| 2 | Ivacaftor | Drug Info | Approved | Cystic fibrosis | [3], [5], [6] | |
| 3 | Lumacaftor + ivacaftor | Drug Info | Approved | Cystic fibrosis | [6] | |
| 4 | Tezacaftor and ivacaftor | Drug Info | Approved | Acute lung injury | [7] | |
| Clinical Trial Drug(s) | [+] 8 Clinical Trial Drugs | + | ||||
| 1 | VX-661 | Drug Info | Phase 3 | Cystic fibrosis | [8] | |
| 2 | ABBV-2222 | Drug Info | Phase 2 | Cystic fibrosis | [6] | |
| 3 | GLPG-1837 | Drug Info | Phase 2 | Cystic fibrosis | [6] | |
| 4 | iOWH032 | Drug Info | Phase 2 | Diarrhea | [9] | |
| 5 | Lumacaftor | Drug Info | Phase 2 | Cystic fibrosis | [10], [11] | |
| 6 | ABBV-2451 | Drug Info | Phase 1 | Cystic fibrosis | [6] | |
| 7 | ABBV-2737 | Drug Info | Phase 1 | Cystic fibrosis | [6] | |
| 8 | ABBV-3067 | Drug Info | Phase 1 | Cystic fibrosis | [6] | |
| Mode of Action | [+] 7 Modes of Action | + | ||||
| Modulator | [+] 6 Modulator drugs | + | ||||
| 1 | Crofelemer | Drug Info | [3], [4] | |||
| 2 | Ivacaftor | Drug Info | [1] | |||
| 3 | ABBV-2222 | Drug Info | [6] | |||
| 4 | ABBV-2451 | Drug Info | [6] | |||
| 5 | ABBV-2737 | Drug Info | [6] | |||
| 6 | ABBV-3067 | Drug Info | [6] | |||
| Enhancer | [+] 2 Enhancer drugs | + | ||||
| 1 | Lumacaftor + ivacaftor | Drug Info | [6] | |||
| 2 | GLPG-1837 | Drug Info | [6] | |||
| Binder | [+] 1 Binder drugs | + | ||||
| 1 | Tezacaftor and ivacaftor | Drug Info | [7] | |||
| Regulator | [+] 2 Regulator drugs | + | ||||
| 1 | VX-661 | Drug Info | [12] | |||
| 2 | Lumacaftor | Drug Info | [14] | |||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | iOWH032 | Drug Info | [13] | |||
| Activator | [+] 6 Activator drugs | + | ||||
| 1 | CBIQ | Drug Info | [15] | |||
| 2 | phenylglycine-01 | Drug Info | [15] | |||
| 3 | sulfonamide-01 | Drug Info | [15] | |||
| 4 | UCCF-029 | Drug Info | [15] | |||
| 5 | UCCF-339 | Drug Info | [15] | |||
| 6 | UCCF-853 | Drug Info | [15] | |||
| Blocker (channel blocker) | [+] 2 Blocker (channel blocker) drugs | + | ||||
| 1 | CFTRinh-172 | Drug Info | [15] | |||
| 2 | GlyH-101 | Drug Info | [15] | |||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 7 KEGG Pathways | + | ||||
| 1 | ABC transporters | |||||
| 2 | cAMP signaling pathway | |||||
| 3 | AMPK signaling pathway | |||||
| 4 | Gastric acid secretion | |||||
| 5 | Pancreatic secretion | |||||
| 6 | Bile secretion | |||||
| 7 | Vibrio cholerae infection | |||||
| Reactome | [+] 1 Reactome Pathways | + | ||||
| 1 | ABC-family proteins mediated transport | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | ABC-family proteins mediated transport | |||||
| References | Top | |||||
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| REF 1 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7453). | |||||
| REF 3 | Nat Rev Drug Discov. 2013 Feb;12(2):87-90. | |||||
| REF 4 | Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from Croton lechleri, targets two distinct intestinal chloride channels. Mol Pharmacol. 2010 Jan;77(1):69-78. | |||||
| REF 5 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4342). | |||||
| REF 6 | Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357. | |||||
| REF 7 | 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89. | |||||
| REF 8 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 9 | ClinicalTrials.gov (NCT02111304) Efficacy of iOWH032 in Dehydrating Cholera. U.S. National Institutes of Health. | |||||
| REF 10 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7481). | |||||
| REF 11 | ClinicalTrials.gov (NCT00865904) Study of VX-809 in Cystic Fibrosis Subjects With the 508-CFTR Gene Mutation. U.S. National Institutes of Health. | |||||
| REF 12 | CFTR Modulators for the Treatment of Cystic Fibrosis. P T. 2014 Jul;39(7):500-11. | |||||
| REF 13 | Developing novel antisecretory drugs to treat infectious diarrhea. Future Med Chem. 2011 Aug;3(10):1317-25. | |||||
| REF 14 | A CFTR corrector (lumacaftor) and a CFTR potentiator (ivacaftor) for treatment of patients with cystic fibrosis who have a phe508del CFTR mutation: a phase 2 randomised controlled trial. Lancet Respir Med. 2014 Jul;2(7):527-38. | |||||
| REF 15 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 707). | |||||
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