Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTRLZHP)

• DTT Name: cAMP-dependent chloride channel (CFTR)
• 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
• Gene Name: CFTR
• DTT Type: Successful target; [1]
• BioChemical Class: ABC transporter
• UniProt ID: CFTR_HUMAN
• TTD ID: T55654
• EC Number: EC 5.6.1.6
• 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
• 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.
• KEGG Pathway:
  ABC transporters (hsa02010)
  cAMP signaling pathway (hsa04024)
  AMPK signaling pathway (hsa04152)
  Gastric acid secretion (hsa04971)
  Pancreatic secretion (hsa04972)
  Bile secretion (hsa04976)
  Vibrio cholerae infection (hsa05110)
• Reactome Pathway: ABC-family proteins mediated transport (R-HSA-382556)
• BioCyc Pathway: MetaCyc:HS00075-MON

Molecular Interaction Atlas (MIA) of This DTT

3 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Crofelemer	DM4AMQZ	HIV-associated diarrhoea	1A2Z	Approved	[2]
Ivacaftor	DMZC1HS	Cystic fibrosis	CA25	Approved	[1]
Tezacaftor and ivacaftor	DMY62FC	Acute lung injury	NB32.3	Approved	[3]

10 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
VX-661	DMJBXO3	Cystic fibrosis	CA25	Phase 3	[4]
ABBV-2222	DM4ZLTY	Cystic fibrosis	CA25	Phase 2	[5]
GLPG-1837	DMOCRYB	Cystic fibrosis	CA25	Phase 2	[5]
iOWH032	DM5TMYC	Diarrhea	ME05.1	Phase 2	[6]
Lumacaftor	DMCLWDJ	Cystic fibrosis	CA25	Phase 2	[7]
QBW251	DMQ5APT	Chronic obstructive pulmonary disease	CA22	Phase 2	[8]
ABBV-2451	DMUCF9L	Cystic fibrosis	CA25	Phase 1	[5]
ABBV-2737	DMU6K37	Cystic fibrosis	CA25	Phase 1	[5]
ABBV-3067	DMB01L5	Cystic fibrosis	CA25	Phase 1	[5]
VX-522	DMO1D9E	Cystic fibrosis	CA25	Phase 1	[9]

8 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CBIQ	DMDIW1M	Discovery agent	N.A.	Investigative	[10]
CFTRinh-172	DM8TJW3	Discovery agent	N.A.	Investigative	[10]
GlyH-101	DM67FQ1	Discovery agent	N.A.	Investigative	[10]
phenylglycine-01	DMHT9AR	Discovery agent	N.A.	Investigative	[10]
sulfonamide-01	DMU0BW9	Discovery agent	N.A.	Investigative	[10]
UCCF-029	DMO9S5P	Discovery agent	N.A.	Investigative	[10]
UCCF-339	DM3I9JG	Discovery agent	N.A.	Investigative	[10]
UCCF-853	DMN9QO4	Discovery agent	N.A.	Investigative	[10]

The Drug Transporter (DTP) Role of This DTT

• DTT DTP Name: Cystic fibrosis transmembrane conductance regulator (ABCC7) DTP Info
• Gene Name: ABCC7

References

• [1] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [2] Nat Rev Drug Discov. 2013 Feb;12(2):87-90.
• [3] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [4] CFTR Modulators for the Treatment of Cystic Fibrosis. P T. 2014 Jul;39(7):500-11.
• [5] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [6] Developing novel antisecretory drugs to treat infectious diarrhea. Future Med Chem. 2011 Aug;3(10):1317-25.
• [7] 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.
• [8] Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251). J Cyst Fibros. 2021 Mar;20(2):250-256.
• [9] Clinical pipeline report, company report or official report of Vertex
• [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. (Target id: 707).