CFTR

Summary

CFTR (CF transmembrane conductance regulator, HGNC:1884) is a protein-coding gene on chromosome 7q31.2, encoding Cystic fibrosis transmembrane conductance regulator (P13569). Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis.

This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome.

Source: NCBI Gene 1080 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cystic fibrosis (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 6,065 total — 927 pathogenic, 395 likely-pathogenic
• Phenotypes (HPO): 103
• Druggable target: yes — 14 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000492

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1884
Approved symbol	CFTR
Name	CF transmembrane conductance regulator
Location	7q31.2
Locus type	gene with protein product
Status	Approved
Aliases	MRP7, ABC35, TNR-CFTR, dJ760C5.1, CFTR/MRP
Ensembl gene	ENSG00000001626
Ensembl biotype	protein_coding
OMIM	602421
Entrez	1080

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 20 protein_coding, 11 protein_coding_CDS_not_defined, 11 nonsense_mediated_decay, 2 retained_intron

ENST00000003084, ENST00000426809, ENST00000429014, ENST00000436097, ENST00000446805, ENST00000468795, ENST00000472848, ENST00000546407, ENST00000600166, ENST00000608965, ENST00000610149, ENST00000621535, ENST00000647639, ENST00000647720, ENST00000647978, ENST00000648260, ENST00000649406, ENST00000649781, ENST00000649850, ENST00000673785, ENST00000685018, ENST00000687278, ENST00000689011, ENST00000692802, ENST00000693465, ENST00000693480, ENST00000699585, ENST00000699596, ENST00000699597, ENST00000699598, ENST00000699599, ENST00000699600, ENST00000699601, ENST00000699602, ENST00000699603, ENST00000699604, ENST00000699605, ENST00000699606, ENST00000889206, ENST00000889207, ENST00000889208, ENST00000889209, ENST00000889210, ENST00000950799

RefSeq mRNA: 1 — MANE Select: NM_000492 NM_000492

CCDS: CCDS5773

Canonical transcript exons

ENST00000003084 — 27 exons

Exon	Start	End
ENSE00000718611	117530899	117531114
ENSE00000718620	117534276	117534365
ENSE00000718626	117535248	117535411
ENSE00000718630	117536548	117536673
ENSE00000718634	117540100	117540346
ENSE00000718637	117542016	117542108
ENSE00000718699	117614613	117614713
ENSE00000977443	117611581	117611808
ENSE00000977444	117666908	117668665
ENSE00001343851	117480025	117480147
ENSE00003833777	117652842	117652931
ENSE00003835972	117665459	117665564
ENSE00003840813	117664688	117664860
ENSE00003925242	117642438	117642593
ENSE00003936498	117627522	117627770
ENSE00003976975	117509034	117509142
ENSE00003976986	117548641	117548823
ENSE00003976987	117504253	117504363
ENSE00003977038	117591934	117592657
ENSE00003977041	117590353	117590439
ENSE00003977044	117602826	117602863
ENSE00003977054	117606674	117606753
ENSE00003977055	117603532	117603782
ENSE00003977056	117610519	117610669
ENSE00003977066	117587739	117587833
ENSE00003977072	117594930	117595058
ENSE00003977079	117559464	117559655

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 99.02.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7950 / max 364.2383, expressed in 193 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
80712	1.4391	176
80713	0.0732	28
80718	0.0586	5
80716	0.0579	4
80715	0.0526	3
80711	0.0262	16
80717	0.0260	3
80720	0.0233	4
80724	0.0171	7
204668	0.0099	2

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	99.02	gold quality
gall bladder	UBERON:0002110	96.99	gold quality
pancreas	UBERON:0001264	96.76	gold quality
rectum	UBERON:0001052	95.92	gold quality
mucosa of sigmoid colon	UBERON:0004993	95.82	gold quality
colonic mucosa	UBERON:0000317	95.77	gold quality
islet of Langerhans	UBERON:0000006	95.45	gold quality
duodenum	UBERON:0002114	95.09	gold quality
mucosa of transverse colon	UBERON:0004991	92.93	gold quality
jejunal mucosa	UBERON:0000399	92.39	gold quality
transverse colon	UBERON:0001157	88.98	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.52	gold quality
minor salivary gland	UBERON:0001830	86.75	gold quality
saliva-secreting gland	UBERON:0001044	86.69	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.40	gold quality
parotid gland	UBERON:0001831	84.91	gold quality
large intestine	UBERON:0000059	83.66	gold quality
intestine	UBERON:0000160	83.25	gold quality
colon	UBERON:0001155	83.14	gold quality
mouth mucosa	UBERON:0003729	82.90	gold quality
spinal cord	UBERON:0002240	82.59	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.57	gold quality
colonic epithelium	UBERON:0000397	81.31	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.14	gold quality
small intestine	UBERON:0002108	81.07	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.67	gold quality
caput epididymis	UBERON:0004358	80.63	gold quality
body of uterus	UBERON:0009853	79.82	gold quality
palpebral conjunctiva	UBERON:0001812	79.80	gold quality
epithelium of bronchus	UBERON:0002031	79.53	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-GEOD-81547	yes	6704.17
E-GEOD-83139	yes	2299.92
E-MTAB-5061	yes	2258.11
E-ENAD-27	yes	2239.71
E-GEOD-81608	yes	963.64
E-GEOD-125970	yes	45.59
E-CURD-114	yes	11.21
E-MTAB-6386	no	13.16
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF1, CDX2, CEBPA, CEBPB, CEBPD, CEBPG, CTCF, CUX1, DNMT1, ESR1, FOXA1, FOXA2, FOXI1, FOXJ1, HIF1A, HNF1A, HNF1B, KAT7, NFE2L2, NFKB1, NFKB, NR3C1, PBX1, RELA, SP1, SP3, SRF, STAT1, TBP, TCF4, TFAP2A, TXK, USF1, USF2, YY1

miRNA regulators (miRDB)

91 targeting CFTR, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-12136	99.98	72.81	5713
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-652-5P	99.91	67.49	505
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-5582-3P	99.86	72.48	4221

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• CFTR gene transcription is regulated by a DNase I hypersensitive site (PMID:10561583)
• mutational analysis of the entire coding region in idiopathic pancreatitis (PMID:11462247)
• TG(m)T(n) polymorphism has an effect on splicing in transgenic mice (PMID:11597137)
• ‘Chronic complications’ reveal mainly the effect of a long-term absence of previously recognized CFTR functions. In contrast, the ‘unique presentations’ provide new insight into the role of CFTR in different tissues. Review. (PMID:11667976)
• disulfide bond structure (PMID:11688981)
• mutations and phylogeny (place of origin) (PMID:11713719)
• wild type CFTR elevates the acid-gated Na(+) current of ASIC1a/2a in part by altering the kinetics of extracellular Na(+) interaction. (PMID:11748227)
• non-conventional trafficking through the early secretory pathway (PMID:11799116)
• Cl(-) channel and a regulator of other transport proteins and the large number of disease-causing CFTR mutations is the reason for a variable genotype-phenotype correlation and sometimes unpredictable clinical manifestation (PMID:11845294)
• CFTR may play a role in regulated secretion by lymphocytes: a new hypothesis for the pathophysiology of cystic fibrosis. (PMID:11845300)
• role for functional CFTR in regulation of lysozyme secretion in human airways. (PMID:11845302)
• actin must be directly associated with CFTR to elicit its activation, further suggesting that this channel protein may bind actin as well. (PMID:11845308)
• CFTR is an apically resident ion channel whose activity is regulated by the activation of the cAMP mediated second messenger cascade. (PMID:11845310)
• Cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels are regulated tightly by protein kinases and phosphatases (PMID:11845311)
• Localisation of wild-type and DeltaF508-CFTR in nasal epithelial cells. (PMID:11845316)
• mapping of DNase I hypersensitive sites (DHS) within the locus (PMID:11856314)
• Cysteine residues in the nucleotide binding domains regulate the conductance state of CFTR channels (PMID:11867445)
• Tyrosine kinase c-Src constitutes a bridge between cystic fibrosis transmembrane regulator channel failure and MUC1 overexpression in cystic fibrosis (PMID:11872746)
• Evidence for direct interaction between actin and the cystic fibrosis transmembrane conductance regulator. (PMID:11908853)
• Discrimination between CF cells and CFTR-corrected epithelial cells by a membrane potential-sensitive probe and digital imaging technique that detects response to cAMP in the majority of CFTR-corrected cells, but only in a small proportion of CF cells. (PMID:11936773)
• data support a model where nucleotide-binding domains form dimers with the ATP-binding sites at the domain-domain interface (PMID:11940532)
• A short segment of the R domain of cystic fibrosis transmembrane conductance regulator contains channel stimulatory and inhibitory activities that are separable by sequence modification (PMID:11950844)
• Protein kinase C epsilon-dependent regulation of cystic fibrosis transmembrane regulator involves binding to a receptor for activated C kinase (RACK1) and RACK1 binding to Na+/H+ exchange regulatory factor. (PMID:11956211)
• calcium channel inhibitors induce surface expression in cystic fibrosis cultured epithelial cells of mutated protein (PMID:11984593)
• Men with the CFTR mutation, the 5T allele only, and those without CFTR mutation have few differences in genital phenotype. Low testicular volume is observed in men without the CFTR mutation and those with the 5T allele only. (PMID:12009340)
• Glutathione levels and BAX activation during apoptosis due to oxidative stress in cells expressing wild-type and mutant protein (PMID:12023951)
• Csp has a role in regulated CFTR trafficking at the plasma membrane. [CYSTEINE STRING PROTEIN] (PMID:12039948)
• Sequence alignment of representative vertebrate CFTR with the aim of generating hypotheses on the functional significance of conserved and variable residues. (PMID:12054472)
• The allele and genotype frequencies of the tetranucleotide tandem repeat (TTR) of CFTR intron 6B were analyzed in eight ethnic populations of the Volga-Ural region, including Bashkir, Tatar, Chuvash, Mari, Mordvinian, Udmurt, Komi-Permyak, and Russian (PMID:12068629)
• Role of Hsp40 co-chaperone Hdj-1 in CFTR turnover with HSP70 (PMID:12069690)
• Introduction of the most common mutations into human P-glycoprotein disrupts packing of the transmembrane segments. (PMID:12070134)
• A novel natural product compound enhances cAMP-regulated chloride conductance of cells expressing CFTR[delta]F508 (PMID:12080183)
• These studies demonstrate that luc-containing YAC vectors can be used to study CFTR expression in human cells, and that regulatory elements responsible for decreased CFTR expression in response to PMA are not located in the 5’-flanking sequence. (PMID:12084577)
• substitution of two residues eliminates aggregation of a 111-amino acid peptide derived from the C-terminal portion of the cystic fibrosis transmembrane conductance regulator (CFTR). (PMID:12084728)
• mutations in CFTR nucleotide binding domain region rescue the CFTRDeltaF508 defect (PMID:12110684)
• The comparison of primary sclerosing cholangitis patients with healthy controls showed no significant difference in the frequency of CFTR mutations (PMID:12127423)
• CFTR gene mutation is observed with trypsinogen levels more than 60 ng/mL. (PMID:12139895)
• CFTR may contribute to blastocoele formation in the early human embryo (PMID:12149408)
• Analysis by mass spectrometry of 100 cystic fibrosis gene mutations in 92 patients with congenital bilateral absence of the vas deferens. Compound heterozygosity. (PMID:12151438)
• CFTR channels are regulated by a t-SNARE complex that may tune CFTR activity to rates of membrane traffic in epithelial cells. (PMID:12209004)

Cross-species orthologs

14 orthologs

Organism	Symbol	Gene ID
danio_rerio	cftr	ENSDARG00000041107
mus_musculus	Cftr	ENSMUSG00000041301
rattus_norvegicus	Cftr	ENSRNOG00000055103
drosophila_melanogaster	l(2)03659	FBGN0010549
drosophila_melanogaster	CG7627	FBGN0032026
drosophila_melanogaster	MRP	FBGN0032456
drosophila_melanogaster	CG9270	FBGN0032908
drosophila_melanogaster	CG10505	FBGN0034612
drosophila_melanogaster	Mrp5	FBGN0038740
drosophila_melanogaster	rdog	FBGN0039644
drosophila_melanogaster	CG11898	FBGN0039645
drosophila_melanogaster	CG31792	FBGN0051792
drosophila_melanogaster	Mrp4	FBGN0263316
caenorhabditis_elegans		WBGENE00000477

Paralogs (11): ABCC8 (ENSG00000006071), ABCC2 (ENSG00000023839), ABCC9 (ENSG00000069431), ABCC6 (ENSG00000091262), ABCC1 (ENSG00000103222), ABCC3 (ENSG00000108846), ABCC5 (ENSG00000114770), ABCC11 (ENSG00000121270), ABCC10 (ENSG00000124574), ABCC4 (ENSG00000125257), ABCC12 (ENSG00000140798)

Protein

Protein identifiers

Cystic fibrosis transmembrane conductance regulator — P13569 (reviewed: P13569)

Alternative names: ATP-binding cassette sub-family C member 7, Channel conductance-controlling ATPase, cAMP-dependent chloride channel

All UniProt accessions (20): A0A3B3IT97, A0A3B3ITE0, A0A3B3ITW0, A0A3B3ITW5, A0A669KBE8, A0A8I5KVL1, A0A8I5KVV2, A0A8I5KXQ9, A0A8V8TNG7, A0A8V8TNH2, A0A8V8TNN0, A0A8V8TNN7, A0A8V8TPV6, A0A8V8TQ89, A0A8V8TQ94, C9J6L5, E7EPB6, P13569, H0Y8A9, M0QYZ3

UniProt curated annotations — full annotation on UniProt →

Function. Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis. Mediates the transport of chloride ions across the cell membrane. Possesses an intrinsic ATPase activity and utilizes ATP to gate its channel; the passive flow of anions through the channel is gated by cycles of ATP binding and hydrolysis by the ATP-binding domains. The ion channel is also permeable to HCO(3)(-); selectivity depends on the extracellular chloride concentration. In vitro, mediates ATP-dependent glutathione flux. 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.

Subunit / interactions. Monomer; does not require oligomerization for channel activity. May form oligomers in the membrane. Interacts with SLC26A3, SLC26A6 and SHANK2. Interacts with NHERF1 and MYO6. Interacts (via C-terminus) with GOPC (via PDZ domain); this promotes CFTR internalization and thereby decreases channel activity. Interacts with SLC4A7 through NHERF1. Found in a complex with MYO5B and RAB11A. Interacts with ANO1. Interacts with SLC26A8. Interacts with AHCYL1; the interaction increases CFTR activity. Interacts with CSE1L. The core-glycosylated form interacts with GORASP2 (via PDZ GRASP-type 1 domain) in respone to ER stress. Interacts with MARCHF2; the interaction leads to CFTR ubiquitination and degradation. Interacts with ADGRG2.

Subcellular location. Apical cell membrane. Early endosome membrane. Cell membrane. Recycling endosome membrane. Endoplasmic reticulum membrane. Nucleus.

Tissue specificity. Expressed in the respiratory airway, including bronchial epithelium, and in the female reproductive tract, including oviduct (at protein level). Detected in pancreatic intercalated ducts in the exocrine tissue, on epithelial cells in intralobular striated ducts in sublingual salivary glands, on apical membranes of crypt cells throughout the small and large intestine, and on the reabsorptive duct in eccrine sweat glands. Detected on the equatorial segment of the sperm head (at protein level). Detected in nasal and bronchial superficial epithelium. Expressed by the central cells on the sebaceous glands, dermal adipocytes and, at lower levels, by epithelial cells.

Post-translational modifications. N-glycosylated. Phosphorylated; cAMP treatment promotes phosphorylation and activates the channel. Dephosphorylation decreases the ATPase activity (in vitro). Phosphorylation at PKA sites activates the channel. Phosphorylation at PKC sites enhances the response to phosphorylation by PKA. Phosphorylated by AMPK; this inhibits channel activity. Ubiquitinated, leading to its degradation in the lysosome. Deubiquitination by USP10 in early endosomes enhances its endocytic recycling to the cell membrane. Ubiquitinated by RNF185 during ER stress. Ubiquitinated by MARCHF2.

Disease relevance. Cystic fibrosis (CF) [MIM:219700] A common generalized disorder of the exocrine glands which impairs clearance of secretions in a variety of organs. It is characterized by the triad of chronic bronchopulmonary disease (with recurrent respiratory infections), pancreatic insufficiency (which leads to malabsorption and growth retardation) and elevated sweat electrolytes. It is the most common genetic disease in Caucasians, with a prevalence of about 1 in 2'000 live births. Inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. There is some evidence that the functional defect caused by the most common variant Phe-508 DEL can be corrected by the binding to the snake phospholipase A2 crotoxin basic subunit CB. This toxin both disrupts the Phe-508 DEL-cytokeratin 8 complex, allowing for the escape from degradation, and increases the chloride channel current. Congenital bilateral absence of the vas deferens (CBAVD) [MIM:277180] An autosomal recessive disease characterized by vas deferens aplasia resulting in azoospermia and male infertility. CBAVD may occur in isolation or as a manifestation of cystic fibrosis. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Binds and hydrolyzes ATP via the two cytoplasmic ABC transporter nucleotide-binding domains. The two ATP-binding domains interact with each other, forming a head-to-tail dimer. Normal ATPase activity requires interaction between the two domains. The first ABC transporter nucleotide-binding domain has no ATPase activity by itself. The PDZ-binding motif mediates interactions with GOPC and with the SLC4A7, NHERF1/EBP50 complex. The R region is intrinsically disordered. It mediates channel activation when it is phosphorylated, but not in the absence of phosphorylation.

Miscellaneous. Exon 9 splicing depends upon 2 polymorphic tracts within intron 8, a T(n) tract and TG(n) tract, where the number of T and/or TG repeats affect the extent of correct splicing of exon 9. Low numbers of T residues and high numbers of TG repeats give rise to less efficient splicing. Transcripts that lack exon 9 sequences fail to mature. Causes congenital bilateral absence of the vas deferens (CBAVD). Alternative acceptor site favored by mutation in an exonic splicing enhancer (ESE). Causes cystic fibrosis (CF).

Similarity. Belongs to the ABC transporter superfamily. ABCC family. CFTR transporter (TC 3.A.1.202) subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P13569-1	1	yes
P13569-2	2
P13569-3	3

RefSeq proteins (1): NP_000483* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003439	ABC_transporter-like_ATP-bd	Domain
IPR003593	AAA+_ATPase	Domain
IPR009147	CFTR/ABCC7	Family
IPR011527	ABC1_TM_dom	Domain
IPR017871	ABC_transporter-like_CS	Conserved_site
IPR025837	CFTR_reg_dom	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036640	ABC1_TM_sf	Homologous_superfamily
IPR047082	CFTR1_ATP-bd_dom1	Domain
IPR050173	ABC_transporter_C-like	Family

Pfam: PF00005, PF00664, PF14396

Enzyme classification (BRENDA):

• EC 2.7.4.3 — adenylate kinase (BRENDA: 73 organisms, 259 substrates, 134 inhibitors, 192 Km, 47 kcat entries)
• EC 5.6.1.6 — channel-conductance-controlling ATPase (BRENDA: 13 organisms, 102 substrates, 71 inhibitors, 16 Km, 3 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
AMP	0.0014–1.9	59
ATP	0.0001–7	58
ADP	0.003–16.8	27
ATP	0.0033–2.2	13
2 ADP	0.006–0.15	5
DAMP	0.507–2	2
2’-DAMP	0.85	1
7-DEAZAADENOSINE 5’-MONOPHOSPHATE	0.73	1
ADP3-	0.03	1
CMP	0.0002	1
MGATP2-	0.15	1

Catalyzed reactions (Rhea), 3 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)
• hydrogencarbonate(in) = hydrogencarbonate(out) (RHEA:28695)
• chloride(in) = chloride(out) (RHEA:29823)

UniProt features (393 total): sequence variant 209, helix 65, strand 29, modified residue 15, topological domain 13, mutagenesis site 13, transmembrane region 12, turn 11, binding site 6, domain 4, region of interest 3, splice variant 3, sequence conflict 2, lipid moiety-binding region 2, glycosylation site 2, chain 1, short sequence motif 1, compositionally biased region 1, cross-link 1

Structure

Experimental structures (PDB)

58 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2PZE	X-RAY DIFFRACTION	1.7
7QI1	X-RAY DIFFRACTION	1.76
2PZG	X-RAY DIFFRACTION	1.8
5TFJ	X-RAY DIFFRACTION	1.85
6WBS	X-RAY DIFFRACTION	1.86
6HEP	X-RAY DIFFRACTION	1.86
5TF8	X-RAY DIFFRACTION	1.86
5TFA	X-RAY DIFFRACTION	1.87
5TFB	X-RAY DIFFRACTION	1.87
5TFD	X-RAY DIFFRACTION	1.89
5TFF	X-RAY DIFFRACTION	1.89
5TFI	X-RAY DIFFRACTION	1.89
5TFG	X-RAY DIFFRACTION	1.91
5TGK	X-RAY DIFFRACTION	1.91
5TFC	X-RAY DIFFRACTION	1.92
5TF7	X-RAY DIFFRACTION	1.93
6GJS	X-RAY DIFFRACTION	1.95
2PZF	X-RAY DIFFRACTION	2
2BBS	X-RAY DIFFRACTION	2.05
4WZ6	X-RAY DIFFRACTION	2.05
5D2D	X-RAY DIFFRACTION	2.1
9MXL	ELECTRON MICROSCOPY	2.1
1XMI	X-RAY DIFFRACTION	2.25
1XMJ	X-RAY DIFFRACTION	2.3
2BBT	X-RAY DIFFRACTION	2.3
6GJQ	X-RAY DIFFRACTION	2.49
2BBO	X-RAY DIFFRACTION	2.55
6GJU	X-RAY DIFFRACTION	2.6
6UK1	X-RAY DIFFRACTION	2.69
3GD7	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P13569-F1	75.96	0.33

Antibody-complex structures (SAbDab): 6 — 6GJQ, 6GJS, 6GJU, 6GK4, 6GKD, 6ZE1

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (6): 401; 434; 458–465; 493; 1219; 1244–1251

Post-translational modifications (18): 549, 660, 670, 686, 700, 712, 717, 737, 753, 768, 790, 795, 813, 1444, 1456, 524, 1395, 688

Glycosylation sites (2): 894, 900

Mutagenesis-validated functional residues (13):

Position	Phenotype
347	decreases glutathione uptake. increases affinity for glutathione.
464	decreases glutathione uptake.
464	impaired maturation of glycan chains indicating impaired trafficking from the endoplasmic reticulum to the cell membrane
508	impaired maturation of glycan chains indicating impaired trafficking from the endoplasmic reticulum to the cell membrane
539	enhances trafficking from the endoplasmic reticulum to the cell membrane.
894	abolishes n-glycosylation, enhances endocytosis and impairs subsequent recycling to the cell surface; when associated wi
900	abolishes n-glycosylation, enhances endocytosis and impairs subsequent recycling to the cell surface; when associated wi
1137	abolishes channel activity. impairs protein maturation, suggesting the protein is retained in the endoplasmic reticulum.
1139	decreases channel activity, no visible effect on protein maturation.
1154	decreases channel activity, no visible effect on protein maturation.
1250	decreases glutathione uptake.
1250	no effect on maturation of glycans, suggesting that trafficking to the plasma membrane is not altered.
1478–1480	reduces interaction with marchf2 and abolishes subsequent marchf2-mediated degradation. no effect on localization to the

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-382556	ABC-family protein mediated transport
R-HSA-5627083	RHO GTPases regulate CFTR trafficking
R-HSA-5678895	Defective CFTR causes cystic fibrosis
R-HSA-5689880	Ub-specific processing proteases
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-9013406	RHOQ GTPase cycle
R-HSA-9613829	Chaperone Mediated Autophagy
R-HSA-9615710	Late endosomal microautophagy
R-HSA-9646399	Aggrephagy
R-HSA-9925563	Developmental Lineage of Pancreatic Ductal Cells

MSigDB gene sets: 498 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MIDORIKAWA_AMPLIFIED_IN_LIVER_CANCER, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOCC_VACUOLAR_MEMBRANE, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOCC_CELL_SURFACE, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_MALE_GAMETE_GENERATION, REACTOME_MEMBRANE_TRAFFICKING, GOBP_TOOTH_MINERALIZATION, GGGTGGRR_PAX4_03, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, KEGG_ABC_TRANSPORTERS, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_SPERM_CAPACITATION

GO Biological Process (23): cholesterol biosynthetic process (GO:0006695), water transport (GO:0006833), bicarbonate transport (GO:0015701), cholesterol transport (GO:0030301), response to endoplasmic reticulum stress (GO:0034976), transepithelial water transport (GO:0035377), sperm capacitation (GO:0048240), multicellular organismal-level water homeostasis (GO:0050891), intracellular pH elevation (GO:0051454), establishment of localization in cell (GO:0051649), transmembrane transport (GO:0055085), membrane hyperpolarization (GO:0060081), positive regulation of enamel mineralization (GO:0070175), cellular response to cAMP (GO:0071320), amelogenesis (GO:0097186), chloride transmembrane transport (GO:1902476), cellular response to forskolin (GO:1904322), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), monoatomic ion transmembrane transport (GO:0034220), regulation of biological quality (GO:0065008), obsolete inorganic ion transmembrane transport (GO:0098660), positive regulation of voltage-gated chloride channel activity (GO:1902943)

GO Molecular Function (18): chloride channel activity (GO:0005254), intracellularly ATP-gated chloride channel activity (GO:0005260), ATP binding (GO:0005524), bicarbonate transmembrane transporter activity (GO:0015106), chloride transmembrane transporter activity (GO:0015108), ATP hydrolysis activity (GO:0016887), chloride channel regulator activity (GO:0017081), chloride channel inhibitor activity (GO:0019869), enzyme binding (GO:0019899), PDZ domain binding (GO:0030165), obsolete ATPase-coupled inorganic anion transmembrane transporter activity (GO:0043225), protein-folding chaperone binding (GO:0051087), 14-3-3 protein binding (GO:0071889), Sec61 translocon complex binding (GO:0106138), ABC-type transporter activity (GO:0140359), nucleotide binding (GO:0000166), protein binding (GO:0005515), isomerase activity (GO:0016853)

GO Cellular Component (21): nucleus (GO:0005634), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), early endosome (GO:0005769), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), endosome membrane (GO:0010008), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), Golgi-associated vesicle membrane (GO:0030660), clathrin-coated endocytic vesicle membrane (GO:0030669), early endosome membrane (GO:0031901), protein-containing complex (GO:0032991), chloride channel complex (GO:0034707), recycling endosome (GO:0055037), recycling endosome membrane (GO:0055038), endosome (GO:0005768), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Autophagy	2
Transport of small molecules	1
RHO GTPase Effectors	1
ABC transporter disorders	1
Deubiquitination	1
Clathrin-mediated endocytosis	1
Membrane Trafficking	1
RHO GTPase cycle	1
Selective autophagy	1
Developmental Cell Lineages of the Exocrine Pancreas	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transport	3
chloride channel activity	3
protein binding	3
endosome	3
cytoplasmic vesicle membrane	2
bounding membrane of organelle	2
plasma membrane region	2
endosome membrane	2
cholesterol metabolic process	1
sterol biosynthetic process	1
secondary alcohol biosynthetic process	1
fluid transport	1
sterol transport	1
cellular response to stress	1
water transport	1
epithelial fluid transport	1
developmental process involved in reproduction	1
spermatid development	1
cellular process involved in reproduction in multicellular organism	1
cell maturation	1
regulation of body fluid levels	1
multicellular organismal-level chemical homeostasis	1
regulation of intracellular pH	1
establishment of localization	1
cellular localization	1
cellular process	1
regulation of membrane potential	1
enamel mineralization	1
positive regulation of tooth mineralization	1
regulation of enamel mineralization	1
response to cAMP	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
odontogenesis of dentin-containing tooth	1
anatomical structure formation involved in morphogenesis	1
chloride transport	1
monoatomic anion transmembrane transport	1
cellular response to lipid	1
cellular response to alcohol	1

Protein interactions and networks

STRING

4858 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CFTR	NHERF1	O14745	996
CFTR	GOPC	Q9HD26	937
CFTR	HSP90AA1	P07900	929
CFTR	HSP90AB1	P08238	925
CFTR	PDZK1	Q5T2W1	920
CFTR	SLC26A6	Q9BXS9	917
CFTR	RNF5	Q99942	898
CFTR	SCNN1B	P51168	896
CFTR	NHERF2	Q15599	891
CFTR	SCNN1G	P51170	886
CFTR	SPINK1	P00995	880
CFTR	SLC26A3	P40879	878
CFTR	SLC26A9	Q7LBE3	874
CFTR	KCNJ1	P48048	871
CFTR	PRSS1	P07477	854

IntAct

860 interactions, top by confidence:

A	B	Type	Score
CFTR	NHERF2	psi-mi:“MI:0915”(physical association)	0.940
NHERF2	CFTR	psi-mi:“MI:0914”(association)	0.940
CFTR	NHERF1	psi-mi:“MI:0407”(direct interaction)	0.940
CFTR	NHERF2	psi-mi:“MI:0407”(direct interaction)	0.940
CFTR	NHERF1	psi-mi:“MI:0914”(association)	0.940
NHERF1	CFTR	psi-mi:“MI:0915”(physical association)	0.940
HSPD1	CFTR	psi-mi:“MI:0915”(physical association)	0.790
PDZK1	CFTR	psi-mi:“MI:0915”(physical association)	0.780
GOPC	CFTR	psi-mi:“MI:0915”(physical association)	0.770
CFTR	CFTR	psi-mi:“MI:0407”(direct interaction)	0.770
CFTR	ACTB	psi-mi:“MI:0915”(physical association)	0.730
CAP1	CFTR	psi-mi:“MI:0915”(physical association)	0.720
CFTR	XPO1	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710

BioGRID (1946): SQSTM1 (Affinity Capture-Western), SQSTM1 (Co-fractionation), EEA1 (Co-fractionation), NEDD4 (Affinity Capture-Western), CFTR (Biochemical Activity), SLC4A7 (Affinity Capture-Western), CFTR (Affinity Capture-Western), HSPB1 (Affinity Capture-Western), CFTR (Biochemical Activity), TFAP2A (Affinity Capture-Western), DAB2 (Affinity Capture-Western), MYO6 (Affinity Capture-Western), Myo6 (Affinity Capture-Western), USP10 (Affinity Capture-Western), CFTR (Affinity Capture-Western)

ESM2 similar proteins: B2RX12, O15438, O15440, O35379, O60706, O88269, O88563, O95255, P13569, P33527, P70170, P82451, P91660, Q00554, Q00555, Q07DZ6, Q07E16, Q09427, Q09428, Q09429, Q28689, Q42093, Q5F364, Q63120, Q63563, Q6UR05, Q6Y306, Q7DM58, Q7GB25, Q80WJ6, Q864R9, Q8CG09, Q8HXQ5, Q8LGU1, Q8VI47, Q8VZZ4, Q92887, Q96J65, Q96J66, Q9C8G9

Diamond homologs: A2XCD4, A7KVC2, B2RX12, E9Q236, F1M3J4, J9VQH1, O15438, O15439, O15440, O35379, O88563, O95255, P13569, P14772, P26361, P26362, P26363, P33527, P34158, P35071, P39109, P53049, P91660, Q00552, Q00553, Q00554, Q00555, Q00PJ2, Q07DV2, Q07DW5, Q07DX5, Q07DY5, Q07DZ6, Q07E16, Q07E42, Q09YH0, Q09YJ4, Q09YK5, Q10185, Q108U0

SIGNOR signaling

38 interactions.

A	Effect	B	Mechanism
GOPC	down-regulates	CFTR	binding
CSNK2A1	up-regulates	CFTR	phosphorylation
CSNK2A1	down-regulates	CFTR	phosphorylation
PRKACA	“down-regulates activity”	CFTR	phosphorylation
PRKG1	up-regulates	CFTR	phosphorylation
ivacaftor	down-regulates	CFTR	“chemical inhibition”
PRKACA	up-regulates	CFTR	phosphorylation
AMPK	“down-regulates activity”	CFTR	phosphorylation
FOXI1	“up-regulates quantity by expression”	CFTR	“transcriptional regulation”
PRKAA1	“down-regulates activity”	CFTR	phosphorylation
STK39	“down-regulates activity”	CFTR	phosphorylation
HSPA8	“down-regulates quantity”	CFTR	binding
RNF5	“down-regulates quantity by destabilization”	CFTR	ubiquitination
STUB1	“down-regulates quantity by destabilization”	CFTR	polyubiquitination
LMTK2	“down-regulates activity”	CFTR	phosphorylation
MARCHF2	“down-regulates quantity by destabilization”	CFTR	ubiquitination
STUB1	“down-regulates quantity by destabilization”	CFTR	ubiquitination
glyburide	“down-regulates activity”	CFTR	“chemical inhibition”
tolbutamide	“down-regulates activity”	CFTR	“chemical inhibition”

Disease & clinical

Clinical variants and AI predictions

ClinVar

6065 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	927
Likely pathogenic	395
Uncertain significance	2427
Likely benign	1468
Benign	71

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1048778	NM_000492.4(CFTR):c.89dup (p.Arg31fs)	Pathogenic
1069281	NM_000492.4(CFTR):c.2560dup (p.Thr854fs)	Pathogenic
1069526	NM_000492.4(CFTR):c.489+1G>A	Pathogenic
1069549	NM_000492.4(CFTR):c.300_301del (p.Leu101fs)	Pathogenic
1070381	NC_000007.13:g.(?117304664)(117306195_?)del	Pathogenic
1070382	NC_000007.13:g.(?117174320)(117176752_?)del	Pathogenic
1074249	NC_000007.13:g.(?117218381)(117254777_?)del	Pathogenic
1074251	NC_000007.13:g.(?117246713)(117251872_?)del	Pathogenic
1185022	NM_000492.4(CFTR):c.2335C>T (p.Gln779Ter)	Pathogenic
1244250	NM_000492.4(CFTR):c.2917C>T (p.Leu973Phe)	Pathogenic
1275739	NM_000492.4(CFTR):c.2620-674_3367+232del	Pathogenic
1300161	NM_000492.3:c.54-5842_489+401del	Pathogenic
1300162	NM_000492.3:c.(273+1_274-1)_(1584+1_1585-1)del	Pathogenic
1300163	NM_000492.4(CFTR):c.761del (p.Lys254fs)	Pathogenic
1300164	NM_000492.4(CFTR):c.580G>A (p.Gly194Arg)	Pathogenic
1300165	NM_000492.4(CFTR):c.3382A>T (p.Arg1128Ter)	Pathogenic
1300166	NM_000492.4(CFTR):c.3600del (p.Asp1201fs)	Pathogenic
1322070	NM_000492.4(CFTR):c.2909-1G>A	Pathogenic
1328993	NM_000492.4(CFTR):c.396del (p.Ile132fs)	Pathogenic
1331481	NC_000007.13:g.(117120202_117144306)_(117149197_117170952)del	Pathogenic
1332860	NM_000492.4(CFTR):c.2848del (p.His950fs)	Pathogenic
1353073	NM_000492.4(CFTR):c.307G>T (p.Gly103Ter)	Pathogenic
1361726	NM_000492.4(CFTR):c.3185_3191del (p.Leu1062fs)	Pathogenic
1373833	NM_000492.4(CFTR):c.831G>A (p.Trp277Ter)	Pathogenic
1374672	NM_000492.4(CFTR):c.3725del (p.Leu1242fs)	Pathogenic
1387407	NM_000492.4(CFTR):c.3736del (p.Thr1246fs)	Pathogenic
1397987	NM_000492.4(CFTR):c.2341C>T (p.Gln781Ter)	Pathogenic
1406009	NM_000492.4(CFTR):c.503C>G (p.Ser168Ter)	Pathogenic
1411468	NM_000492.4(CFTR):c.3322del (p.Val1108fs)	Pathogenic
1418949	NM_000492.4(CFTR):c.922_926del (p.Ser308fs)	Pathogenic

SpliceAI

9348 predictions. Top by Δscore:

Variant	Effect	Δscore
7:117297607:CTTA:C	donor_loss	1.0000
7:117297608:TTA:T	donor_loss	1.0000
7:117297609:TA:T	donor_loss	1.0000
7:117297610:A:AC	donor_gain	1.0000
7:117297610:AC:A	donor_gain	1.0000
7:117297610:ACCT:A	donor_loss	1.0000
7:117297610:ACCTG:A	donor_gain	1.0000
7:117297611:C:CC	donor_gain	1.0000
7:117297611:C:CT	donor_loss	1.0000
7:117297611:CC:C	donor_gain	1.0000
7:117297611:CCT:C	donor_gain	1.0000
7:117297611:CCTG:C	donor_gain	1.0000
7:117297611:CCTGC:C	donor_gain	1.0000
7:117297877:C:A	acceptor_loss	1.0000
7:117297878:T:A	acceptor_loss	1.0000
7:117297881:C:CT	acceptor_gain	1.0000
7:117315073:T:A	donor_gain	1.0000
7:117379932:TTTTA:T	donor_loss	1.0000
7:117379933:TTTAC:T	donor_loss	1.0000
7:117379934:TTAC:T	donor_loss	1.0000
7:117379935:TACC:T	donor_loss	1.0000
7:117379936:A:AC	donor_gain	1.0000
7:117379936:ACCT:A	donor_loss	1.0000
7:117379937:C:CC	donor_gain	1.0000
7:117380043:CCATT:C	acceptor_gain	1.0000
7:117380044:CATT:C	acceptor_gain	1.0000
7:117380044:CATTC:C	acceptor_gain	1.0000
7:117380045:ATT:A	acceptor_gain	1.0000
7:117380045:ATTC:A	acceptor_loss	1.0000
7:117380045:ATTCT:A	acceptor_gain	1.0000

AlphaMissense

9721 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:117611613:A:C	S1058R	0.999
7:117611615:C:A	S1058R	0.999
7:117611615:C:G	S1058R	0.999
7:117614693:A:C	S1150R	0.999
7:117614695:C:A	S1150R	0.999
7:117614695:C:G	S1150R	0.999
7:117535272:T:A	W202R	0.998
7:117535272:T:C	W202R	0.998
7:117610649:T:C	L1040P	0.998
7:117611686:T:C	L1082P	0.998
7:117509038:T:A	W57R	0.997
7:117509038:T:C	W57R	0.997
7:117531097:A:C	S158R	0.997
7:117531099:T:A	S158R	0.997
7:117531099:T:G	S158R	0.997
7:117559586:T:A	N505K	0.997
7:117559586:T:G	N505K	0.997
7:117559648:T:C	L526P	0.997
7:117611638:G:C	R1066P	0.997
7:117559557:T:A	W496R	0.996
7:117559557:T:C	W496R	0.996
7:117587830:C:A	A559E	0.996
7:117590354:G:C	A561P	0.996
7:117590360:T:G	Y563D	0.996
7:117590378:T:G	Y569D	0.996
7:117611637:C:A	R1066S	0.996
7:117664695:T:C	L1324P	0.996
7:117559641:T:C	C524R	0.995
7:117587799:A:C	S549R	0.995
7:117587801:T:A	S549R	0.995

dbSNP variants (sampled 300 via entrez): RS1000031545 (7:117537165 T>C), RS1000034626 (7:117582064 T>C), RS1000037328 (7:117510927 G>A,C), RS1000041223 (7:117495128 G>A), RS1000052559 (7:117487754 A>G), RS1000053950 (7:117630274 T>C), RS1000056210 (7:117488395 T>G), RS1000083304 (7:117622098 G>T), RS1000101644 (7:117582439 C>T), RS1000104500 (7:117486210 G>A,C), RS1000104971 (7:117592650 A>G), RS1000120898 (7:117628420 A>G), RS1000124458 (7:117513924 T>C), RS1000161899 (7:117480911 T>C), RS1000190390 (7:117617945 C>T)

Disease associations

OMIM: gene MIM:602421 | disease phenotypes: MIM:219700, MIM:211400, MIM:277180, MIM:167800, MIM:415000, MIM:181500, MIM:606719, MIM:193300, MIM:614844

GenCC curated gene-disease

Disease	Classification	Inheritance
cystic fibrosis	Definitive	Autosomal recessive
congenital bilateral absence of vas deferens	Supportive	Autosomal recessive
hereditary chronic pancreatitis	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
cystic fibrosis	Definitive	AR

Mondo (19): cystic fibrosis (MONDO:0009061), CFTR-related disorder (MONDO:7770004), bronchiectasis with or without elevated sweat chloride 1 (MONDO:0008887), congenital bilateral aplasia of vas deferens from CFTR mutation (MONDO:0010178), hereditary chronic pancreatitis (MONDO:0008185), spermatogenic failure, Y-linked, 2 (MONDO:0010767), schizophrenia (MONDO:0005090), chronic pancreatitis (MONDO:0005003), infertility disorder (MONDO:0005047), congenital bilateral absence of vas deferens (MONDO:0018801), chronic rhinosinusitis (MONDO:0006031), male infertility (MONDO:0005372), melanoma-pancreatic cancer syndrome (MONDO:0011713), von Hippel-Lindau disease (MONDO:0008667), pancreatitis (MONDO:0004982)

Orphanet (10): Cystic fibrosis (Orphanet:586), Idiopathic bronchiectasis (Orphanet:60033), Congenital bilateral absence of vas deferens (Orphanet:48), Autosomal dominant hereditary chronic pancreatitis (Orphanet:676), Chromosome Y microdeletion syndrome (Orphanet:1646), Familial atypical multiple mole melanoma syndrome (Orphanet:404560), Cystic hygroma (Orphanet:79486), Von Hippel-Lindau disease (Orphanet:892), Joubert syndrome with oculorenal defect (Orphanet:2318), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

103 total (30 of 103 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000027	Azoospermia
HP:0000118	Phenotypic abnormality
HP:0000122	Unilateral renal agenesis
HP:0000246	Sinusitis
HP:0000365	Hearing impairment
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000787	Nephrolithiasis
HP:0000798	Oligozoospermia
HP:0000819	Diabetes mellitus
HP:0000837	Increased circulating gonadotropin level
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000969	Edema
HP:0000982	Palmoplantar keratoderma
HP:0001047	Atopic dermatitis
HP:0001217	Clubbing
HP:0001392	Abnormality of the liver
HP:0001394	Cirrhosis
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001648	Cor pulmonale
HP:0001658	Myocardial infarction
HP:0001733	Pancreatitis
HP:0001738	Exocrine pancreatic insufficiency
HP:0001944	Dehydration
HP:0001945	Fever
HP:0001977	Abnormal thrombosis

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001356_23	Gout	1.000000e-07
GCST001629_2	Response to platinum-based chemotherapy in non-small-cell lung cancer	4.000000e-07
GCST002408_2	Response to methotrexate in juvenile idiopathic arthritis	5.000000e-07
GCST002408_3	Response to methotrexate in juvenile idiopathic arthritis	6.000000e-06
GCST003740_3	Barrett’s esophagus or Esophageal adenocarcinoma	5.000000e-10
GCST005956_17	Waist-to-hip ratio adjusted for BMI	5.000000e-09
GCST005962_49	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	3.000000e-07
GCST006395_30	Glaucoma	3.000000e-08
GCST90014023_24	Type 1 diabetes	2.000000e-16

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

MeSH disease descriptors (13)

Descriptor	Name	Tree numbers
D001943	Breast Neoplasms	C04.588.180; C17.800.090.500
D003550	Cystic Fibrosis	C06.689.202; C08.381.187; C16.320.190; C16.614.213
D007246	Infertility	C12.100.750
D007248	Infertility, Male	C12.100.500.430; C12.100.750.700; C12.200.294.430
D008531	Megacolon	C06.405.469.158.701
D009298	Nasal Polyps	C08.460.572; C09.603.557; C23.300.825.557
D010195	Pancreatitis	C06.689.750
D050500	Pancreatitis, Chronic	C06.689.750.830; C23.550.291.500.750
D006623	von Hippel-Lindau Disease	C10.562.925; C14.907.077.925; C16.131.077.245.750; C16.320.184.750
C567618	Bronchiectasis With Or Without Elevated Sweat Chloride 1 (supp.)
C537262	Hereditary pancreatitis (supp.)
C563985	Melanoma-Pancreatic Cancer Syndrome (supp.)
C564030	Spermatogenic Failure, Nonobstructive, Y-Linked (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3885559 (PROTEIN-PROTEIN INTERACTION), CHEMBL4051 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

14 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 238,049 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2010601	IVACAFTOR	4	2,662
CHEMBL2103870	LUMACAFTOR	4	2,367
CHEMBL3544914	TEZACAFTOR	4	1,466
CHEMBL4298128	ELEXACAFTOR	4	547
CHEMBL472	GLYBURIDE	4	53,236
CHEMBL226335	RUTIN	3	57,988
CHEMBL4297849	BAMOCAFTOR	3	272
CHEMBL50	QUERCETIN	3	74,559
CHEMBL4101487	GALICAFTOR	2	301
CHEMBL44	GENISTEIN	2	44,212
CHEMBL4650318	ICENTICAFTOR	2	241
CHEMBL4802150	NAVOCAFTOR	2	151
CHEMBL6068031	RISELCAFTOR	2	2
CHEMBL6068548	GLPG-2737	2	45

PharmGKB: 1 entry (VIP=true, CPIC=true)

PharmGKB clinical annotations

78 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs113993958	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs113993959	Other	3	ataluren	Cystic Fibrosis
rs113993960	Efficacy	1A	ivacaftor / lumacaftor	Cystic Fibrosis
rs113993960	Efficacy	1A	ivacaftor / tezacaftor	Cystic Fibrosis
rs113993960	Toxicity	3	ivacaftor / lumacaftor	Cystic Fibrosis
rs113993960	Efficacy	3	cysteamine	Cystic Fibrosis
rs113993960	Efficacy	3	lumacaftor	Cystic Fibrosis
rs113993960	Efficacy	3	cavosonstat	Cystic Fibrosis
rs113993960	Efficacy	4	ivacaftor	Cystic Fibrosis
rs115545701	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs11971167	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs121908751	Efficacy	1A	elexacaftor / tezacaftor / ivacaftor	Cystic Fibrosis
rs121908752	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs121908753	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs121908755	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs121908757	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs121909005	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs121909011	Efficacy	3	ivacaftor / lumacaftor	Cystic Fibrosis
rs121909011	Efficacy	3	ivacaftor	Cystic Fibrosis
rs121909011	Efficacy	3	elexacaftor / tezacaftor / ivacaftor	Cystic Fibrosis
rs121909013	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs121909019	Efficacy	3	ivacaftor	Cystic Fibrosis
rs121909019	Efficacy	3	elexacaftor / tezacaftor / ivacaftor	Cystic Fibrosis
rs121909020	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs121909041	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs121909047	Efficacy	3	lumacaftor	Cystic Fibrosis
rs121909047	Efficacy	3	ivacaftor	Cystic Fibrosis
rs121909047	Efficacy	3	elexacaftor / tezacaftor / ivacaftor	Cystic Fibrosis
rs141033578	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs150212784	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs1800076	Efficacy	1A	elexacaftor / tezacaftor / ivacaftor;ivacaftor	Cystic Fibrosis
rs1800100	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs1800111	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs186045772	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs186089140	Efficacy	1A	elexacaftor / tezacaftor / ivacaftor;ivacaftor	Cystic Fibrosis
rs193922525	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs202179988	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs267606723	Efficacy	1A	ivacaftor	Cystic Fibrosis
rs34911792	Efficacy	3	ivacaftor	Cystic Fibrosis
rs35516286	Efficacy	1A	elexacaftor / tezacaftor / ivacaftor;ivacaftor	Cystic Fibrosis

PharmGKB variants

134 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs74503330	CFTR	1A	202.00	1	ivacaftor
rs74597325	CFTR		0.00	0
rs74767530	CFTR		0.00	0
rs75039782	CFTR	1A	200.00	2	elexacaftor / tezacaftor / ivacaftor;ivacaftor;ataluren
rs75527207	CFTR	1A	237.62	2	ivacaftor;ivacaftor;tezacaftor
rs77010898	CFTR	3	4.50	3	ataluren;curcumin;ivacaftor;ivacaftor
rs78655421	CFTR	1A	206.25	1	ivacaftor
rs80282562	CFTR	1A	202.00	1	ivacaftor
rs113993959	CFTR	3	4.50	1	ataluren
rs113993960	CFTR	1A	123.38	7	lumacaftor;ivacaftor / tezacaftor;ivacaftor;cavosonstat;cysteamine;ivacaftor / lumacaftor
rs121908755	CFTR	1A	202.50	1	ivacaftor
rs121908757	CFTR	1A	204.75	1	ivacaftor
rs121909005	CFTR	1A	202.25	1	ivacaftor
rs121909013	CFTR	1A	202.00	1	ivacaftor
rs121909041	CFTR	1A	202.00	1	ivacaftor
rs193922525	CFTR	1A	202.00	1	ivacaftor
rs267606723	CFTR	1A	202.00	1	ivacaftor
rs77932196	CFTR	1A	201.25	2	elexacaftor / tezacaftor / ivacaftor;ivacaftor
rs121909011	CFTR	3	1.50	3	ivacaftor / lumacaftor;ivacaftor;elexacaftor / tezacaftor / ivacaftor
rs80034486	CFTR	3	2.88	1	elexacaftor / tezacaftor / ivacaftor
rs80224560	CFTR	1A	200.25	1	elexacaftor / tezacaftor / ivacaftor;ivacaftor
rs75961395	CFTR	3	0.62	1	elexacaftor / tezacaftor / ivacaftor
rs121908745	CFTR		0.00	0
rs80055610	CFTR		0.00	0
rs74551128	CFTR	1A	200.00	2	ivacaftor;ivacaftor / lumacaftor
rs397508256	CFTR	1A	200.00	1	ivacaftor
rs368505753	CFTR	1A	200.00	1	ivacaftor
rs115545701	CFTR	1A	200.00	1	ivacaftor
rs397508537	CFTR	1A	200.00	1	ivacaftor
rs113993958	CFTR	1A	200.00	1	ivacaftor
rs77834169	CFTR	1A	200.00	1	ivacaftor
rs397508759	CFTR	1A	200.00	1	ivacaftor
rs121908752	CFTR	1A	200.00	1	ivacaftor
rs121908753	CFTR	1A	200.00	1	ivacaftor
rs397508288	CFTR	1A	200.00	1	ivacaftor
rs397508442	CFTR	1A	200.25	1	ivacaftor
rs141033578	CFTR	1A	200.00	1	ivacaftor
rs150212784	CFTR	1A	200.00	1	ivacaftor
rs397508513	CFTR	1A	200.00	1	ivacaftor
rs121909020	CFTR	1A	200.00	1	ivacaftor

PharmGKB dosing guidelines

2 guidelines.

Source	Drug	Guideline	Dosing?	Recommendation?
CPIC	ivacaftor	Annotation of CPIC Guideline for ivacaftor and CFTR		yes
CFF	ivacaftor	Annotation of CFF Guideline for ivacaftor and CFTR		yes

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other ic — CFTR

Most potent curated ligand interactions (17 total), top 17:

Ligand	Action	Affinity	Parameter
ivacaftor	Potentiation	8.52	pEC50
(R)-BPO-27	Inhibition	8.4	pIC50
felodipine	Potentiation	8.4	pKi
compound 16d [PMID: 36573286]	Activation	7.64	pEC50
bamocaftor	Binding	7.52	pEC50
icenticaftor	Potentiation	7.33	pEC50
elexacaftor	Activator	7.15	pEC50
CFTRinh-172	Inhibition	7.1	pIC50
GaTx1	Inhibition	7.0	pIC50
GLPG1837	Potentiation	6.64	pEC50
deutivacaftor	Potentiation	6.59	pEC50
tezacaftor	Activator	6.57	pEC50
GLPG2737	Activator	6.16	pEC50
lumacaftor	Binding	5.59	pEC50
GlyH-101	Pore blocker	5.37	pIC50
crofelemer	Inhibition	5.15	pIC50
glibenclamide	Pore blocker	4.66	pKi

Binding affinities (BindingDB)

78 measured of 194 human assays (196 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
BDBM301432	EC50	0.2 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile,enantiomer 1	EC50	0.4 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile	EC50	0.41 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-7-[1-[1-(2-fluorophenyl)pyrazol-4-yl]ethyl]-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile	EC50	0.42 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
BDBM301434	EC50	0.42 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-7-{[1-(2-fluorophenyl)-1H-pyrazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile	EC50	0.57 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-7-{(1R)-1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile,enantiomer 2	EC50	0.66 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
1-[1-[1-(2-fluorophenyl)pyrazol-4-yl]propyl]-3-[2-(trifluoromethyl)pyrimidin-5-yl]pyrazolo[3,4-d]pyrimidin-4-amine	EC50	1.53 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-7-{1-[3-(2-fluorophenyl)-1,2-oxazol-5-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, enantiomer 1	EC50	1.67 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
7-[1-[1-(2-fluorophenyl)triazol-4-yl]propyl]-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine	EC50	1.88 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile,enantiomer 1	EC50	2.13 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-5-[2-(difluoromethyl)pyrimidin-5-yl]-7-{1-[1-(2-fluorophenyl)-1H-pyrazol-4-yl]ethyl}pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile,enantiomer 2	EC50	3.87 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-Amino-7-{[3-(2-fluorophenyl)-1,2-oxazol-5-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile	EC50	4 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-7-{1-[1-(propan-2-yl)-1H-pyrazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile,enantiomer 1	EC50	4.17 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
3-amino-N-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5,6-bis(trifluoromethyl)pyridine-2-carboxamide	EC50	8 nM	US-10117858: Pyridine and pyrazine derivative for the treatment of CF
3-amino-N-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5,6-bis(trifluoromethyl)pyridine-2-carboxamide	EC50	10 nM	US-10117858: Pyridine and pyrazine derivative for the treatment of CF
7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine,enantiomer 1	EC50	10.4 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile,enantiomer 1	EC50	10.6 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-7-[1-[1-(2-fluorophenyl)triazol-4-yl]ethyl]-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile	EC50	11.2 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-7-{1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile,enantiomer 2	EC50	13 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
3-amino-6-bromo-N-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5-(trifluoromethyl)pyridine-2-carboxamide	EC50	15 nM	US-10117858: Pyridine and pyrazine derivative for the treatment of CF
7-{1-[1-(2-Fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine	EC50	16 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
7-[1-[1-(2,5-difluorophenyl)triazol-4-yl]propyl]-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine	EC50	17.6 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
7-{1-[1-(2,5-difluorophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine,enantiomer 1	EC50	19.8 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile	EC50	23.3 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-7-{1-[1-(3,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile,enantiomer 2	EC50	28.4 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
1-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine,enantiomer 1	EC50	29.2 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
LOVASTATIN	IC50	29.5 nM	US-9353061: 3,5,N-trihydroxy-alkanamide and derivatives: method for making same and use thereof
4-Amino-7-{1-[1-(2,4-difluorophenyl)-1H-pyrazol-4-yl]ethyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile, enantiomers 1 and 2	EC50	30 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
4-amino-7-{1-[1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazine-6-carbonitrile,enantiomer 1	EC50	33.5 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxypropyl)-5-(trifluoromethyl)pyridine-2-carboxamide	EC50	35 nM	US-10117858: Pyridine and pyrazine derivative for the treatment of CF
3-amino-6-(4-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)pyridine-2-carboxamide	EC50	37 nM	US-10117858: Pyridine and pyrazine derivative for the treatment of CF
N-[2-tert-butyl-1-[2-(dimethylamino)ethyl]-6-fluoroindol-5-yl]-1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropane-1-carboxamide	EC50	38.1 nM	US-10022352: Modulators of ATP-binding cassette transporters
N-[2-tert-butyl-1-[(2R)-2,3-dihydroxypropyl]indol-5-yl]-1-(4-methoxyphenyl)-2,2-dimethylcyclopropane-1-carboxamide	EC50	39.1 nM	US-10022352: Modulators of ATP-binding cassette transporters
3-amino-6-(4-fluorophenyl)-N-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5-(trifluoromethyl)pyridine-2-carboxamide	EC50	40 nM	US-10117858: Pyridine and pyrazine derivative for the treatment of CF
3-amino-6-methoxy-N-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5-(trifluoromethyl)pyridine-2-carboxamide	EC50	50 nM	US-10117858: Pyridine and pyrazine derivative for the treatment of CF
1-[1-(1-phenyl-1H-1,2,3-triazol-4-yl)propyl]-3-[2-(trifluoromethyl)pyrimidin-5-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine,enantiomer 1	EC50	50.3 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
3-amino-6-(6-methyl-3-pyridinyl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)pyridine-2-carboxamide	EC50	51 nM	US-10117858: Pyridine and pyrazine derivative for the treatment of CF
3-amino-6-bromo-N-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5-(trifluoromethyl)pyridine-2-carboxamide	EC50	55 nM	US-10117858: Pyridine and pyrazine derivative for the treatment of CF
3-amino-6-(4-fluorophenyl)-N-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5-(trifluoromethyl)pyridine-2-carboxamide	EC50	60 nM	US-10117858: Pyridine and pyrazine derivative for the treatment of CF
1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-[1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)indol-5-yl]cyclopropane-1-carboxamide	EC50	81.8 nM	US-10022352: Modulators of ATP-binding cassette transporters
1-(4-fluorophenyl)-N-(2-methoxyethylsulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-propan-2-ylpyrazolo[5,4-b]pyridine-6-carboxamide	IC50	102 nM	US-10130622: Compounds for treatment of cystic fibrosis
3-amino-6-(2,4-dichlorophenyl)-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)pyridine-2-carboxamide	EC50	112 nM	US-10117858: Pyridine and pyrazine derivative for the treatment of CF
3-amino-6-(6-methyl-3-pyridinyl)-N-[3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl]-5-(trifluoromethyl)pyridine-2-carboxamide	EC50	115 nM	US-10117858: Pyridine and pyrazine derivative for the treatment of CF
7-[1-[1-(2,4-difluorophenyl)triazol-4-yl]propyl]-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine	EC50	115 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
5-(4-Chlorophenyl)-7-{[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]methyl}imidazo[5,1-f][1,2,4]triazin-4-amine trifluoroacetate	EC50	116 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
7-{1-[1-(2-fluorophenyl)-1H-1,2,3-triazol-4-yl]propyl}-5-(4-methoxypyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine,enantiomer 2	EC50	123 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
CHEMBL5204350	EC50	136 nM
1-[4-amino-5-[2-(trifluoromethyl)pyrimidin-5-yl]pyrrolo[2,1-f][1,2,4]triazin-7-yl]-1-[1-(2-fluorophenyl)triazol-4-yl]ethanol	EC50	147 nM	US-10131670: Bicyclic heteroaryl derivatives as CFTR potentiators
1-(1,3-benzodioxol-5-yl)-N-[2-tert-butyl-1-[(2R)-2,3-dihydroxypropyl]-6-fluoroindol-5-yl]cyclopropane-1-carboxamide	EC50	160 nM	US-10022352: Modulators of ATP-binding cassette transporters

ChEMBL bioactivities

1202 potent at pChembl≥5 of 1359 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.70	EC50	0.2	nM	CHEMBL5863288
9.40	EC50	0.4	nM	CHEMBL5178232
9.40	EC50	0.4	nM	CHEMBL5861582
9.39	EC50	0.41	nM	CHEMBL5802461
9.38	EC50	0.42	nM	CHEMBL6033456
9.38	EC50	0.42	nM	CHEMBL5892004
9.30	EC50	0.5	nM	CHEMBL4558190
9.29	EC50	0.51	nM	CHEMBL5193680
9.27	EC50	0.54	nM	CHEMBL4084934
9.25	EC50	0.56	nM	CHEMBL5863288
9.25	EC50	0.56	nM	CHEMBL5892004
9.24	EC50	0.57	nM	CHEMBL6009312
9.21	EC50	0.62	nM	CHEMBL6033456
9.18	EC50	0.66	nM	CHEMBL5178488
9.18	EC50	0.66	nM	CHEMBL5881985
9.10	EC50	0.8	nM	CHEMBL5202275
9.08	EC50	0.84	nM	CHEMBL5186971
9.07	EC50	0.86	nM	CHEMBL6009312
9.05	EC50	0.9	nM	CHEMBL5171054
8.98	EC50	1.05	nM	CHEMBL5802461
8.96	EC50	1.1	nM	CHEMBL4799994
8.96	EC50	1.1	nM	CHEMBL6170767
8.81	EC50	1.53	nM	CHEMBL5860580
8.80	EC50	1.6	nM	CHEMBL6170689
8.78	EC50	1.67	nM	CHEMBL5889215
8.74	EC50	1.8	nM	CHEMBL6143326
8.73	EC50	1.88	nM	CHEMBL6000653
8.70	EC50	2	nM	CHEMBL3357142
8.70	EC50	2	nM	CHEMBL4087529
8.70	EC50	2	nM	CHEMBL4066158
8.70	EC50	2	nM	CHEMBL5863288
8.70	EC50	2	nM	CHEMBL6000653
8.70	EC50	2	nM	CHEMBL5869365
8.70	EC50	2	nM	CHEMBL6175200
8.70	EC50	2	nM	CHEMBL6167971
8.70	EC50	2	nM	CHEMBL6148174
8.67	EC50	2.13	nM	CHEMBL5964878
8.57	EC50	2.7	nM	CHEMBL4102980
8.57	EC50	2.7	nM	CHEMBL4083374
8.55	EC50	2.8	nM	CHEMBL4787310
8.52	EC50	3	nM	IVACAFTOR
8.52	EC50	3	nM	CHEMBL3357143
8.52	EC50	3	nM	CHEMBL3357141
8.52	EC50	3	nM	CHEMBL4103906
8.52	EC50	3	nM	CHEMBL4075348
8.52	EC50	3.02	nM	CHEMBL5964878
8.52	EC50	3	nM	CHEMBL5892004
8.52	EC50	3	nM	CHEMBL6171349
8.52	EC50	3	nM	CHEMBL4077574
8.51	EC50	3.1	nM	CHEMBL5889215

PubChem BioAssay actives

930 with measured affinity, of 2617 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-amino-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-5-[2-(trifluoromethoxy)phenyl]sulfonylpyridine-2-carboxamide	1744464: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o- cells co-expressing YFP incubated for 10 mins by halide potentiator assay	ec50	0.0003	uM
2-[6-(difluoromethyl)-2-pyridinyl]-1-(2-methoxy-5-methylphenyl)-N-(2-methylquinolin-5-yl)sulfonylcyclopropane-1-carboxamide	1875523: Modulation of homozygous F508del/F508del CFTR mutant in HBE cells incubated for 18 to 24 hrs by trans-epithelial current clamp assay	ec50	0.0004	uM
2-[(2-hydroxy-4,4-dimethylpentanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide	1471893: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o cells incubated for 10 mins in presence of forskolin measured for 7 secs by YFP halide assay	ec50	0.0005	uM
4-[4-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid	1570126: Corrector activity at CFTR F508del mutant (unknown origin)	ec50	0.0005	uM
1-(2-methoxy-5-methylphenyl)-N-(2-methylquinolin-5-yl)sulfonyl-2-[3-(trifluoromethyl)phenyl]cyclopropane-1-carboxamide	1875523: Modulation of homozygous F508del/F508del CFTR mutant in HBE cells incubated for 18 to 24 hrs by trans-epithelial current clamp assay	ec50	0.0005	uM
1-(2-methoxy-5-methylphenyl)-2-(4-methoxyphenyl)-N-(2-methylquinolin-5-yl)sulfonylcyclopropane-1-carboxamide	1875523: Modulation of homozygous F508del/F508del CFTR mutant in HBE cells incubated for 18 to 24 hrs by trans-epithelial current clamp assay	ec50	0.0007	uM
1-(2-methoxy-5-methylphenyl)-2-(3-methoxyphenyl)-N-(2-methylquinolin-5-yl)sulfonylcyclopropane-1-carboxamide	1875523: Modulation of homozygous F508del/F508del CFTR mutant in HBE cells incubated for 18 to 24 hrs by trans-epithelial current clamp assay	ec50	0.0008	uM
1-(2-methoxy-5-methylphenyl)-2-(4-methylphenyl)-N-(2-methylquinolin-5-yl)sulfonylcyclopropane-1-carboxamide	1875523: Modulation of homozygous F508del/F508del CFTR mutant in HBE cells incubated for 18 to 24 hrs by trans-epithelial current clamp assay	ec50	0.0008	uM
1-(2-methoxy-5-methylphenyl)-N-(2-methylquinolin-5-yl)sulfonyl-2-(6-propan-2-yloxy-2-pyridinyl)cyclopropane-1-carboxamide	1875523: Modulation of homozygous F508del/F508del CFTR mutant in HBE cells incubated for 18 to 24 hrs by trans-epithelial current clamp assay	ec50	0.0009	uM
[3-amino-5-(4-fluorophenyl)sulfonyl-2-pyridinyl]-[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone	1744464: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o- cells co-expressing YFP incubated for 10 mins by halide potentiator assay	ec50	0.0011	uM
N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-methyl-1H-pyrazole-5-carboxamide	1471893: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o cells incubated for 10 mins in presence of forskolin measured for 7 secs by YFP halide assay	ec50	0.0020	uM
N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-1H-pyrazole-5-carboxamide	1471893: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o cells incubated for 10 mins in presence of forskolin measured for 7 secs by YFP halide assay	ec50	0.0020	uM
N-(4-tert-butyl-2-fluoro-5-hydroxyphenyl)-4-oxo-1H-quinoline-3-carboxamide	1172572: Potentiation of human CFTR F508del mutant expressed in mouse NIH-3T3 cells after 30 mins by fluorescent voltage sensing optical assay	ec50	0.0020	uM
N,N-dibenzyl-4-oxo-1H-quinoline-3-carboxamide	1979275: Inhibition of CFTR F508 deletion mutant (unknown origin)	ec50	0.0021	uM
2-[[(2S)-2-hydroxy-3,3-dimethylbutanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide	1471893: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o cells incubated for 10 mins in presence of forskolin measured for 7 secs by YFP halide assay	ec50	0.0027	uM
3-amino-N-[(1-hydroxycyclopropyl)methyl]-5-[4-(trifluoromethoxy)phenyl]sulfonylpyridine-2-carboxamide	1744464: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o- cells co-expressing YFP incubated for 10 mins by halide potentiator assay	ec50	0.0028	uM
N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide	1471893: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o cells incubated for 10 mins in presence of forskolin measured for 7 secs by YFP halide assay	ec50	0.0030	uM
N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide	1471893: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o cells incubated for 10 mins in presence of forskolin measured for 7 secs by YFP halide assay	ec50	0.0030	uM
Ivacaftor	1170917: Corrector activity at CFTR mutant (unknown origin) by phenotypic screening assay	ec50	0.0030	uM
N-(4-tert-butyl-3-hydroxyphenyl)-4-oxo-1H-quinoline-3-carboxamide	1172572: Potentiation of human CFTR F508del mutant expressed in mouse NIH-3T3 cells after 30 mins by fluorescent voltage sensing optical assay	ec50	0.0030	uM
N-[4-tert-butyl-5-hydroxy-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide	1172572: Potentiation of human CFTR F508del mutant expressed in mouse NIH-3T3 cells after 30 mins by fluorescent voltage sensing optical assay	ec50	0.0030	uM
3-amino-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-5-[4-(trifluoromethoxy)phenyl]sulfonylpyridine-2-carboxamide	1744464: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o- cells co-expressing YFP incubated for 10 mins by halide potentiator assay	ec50	0.0034	uM
(3S)-2-(4-methoxy-3-propan-2-yloxybenzoyl)-N-(4-pentylphenyl)-3,4-dihydro-1H-isoquinoline-3-carboxamide	246453: Effective concentration for cellular chloride transport in C127 mouse epithelial cell transfected with recombinant Delta F508 CFTR	ec50	0.0035	uM
2-[(2-hydroxybenzoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide	1471893: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o cells incubated for 10 mins in presence of forskolin measured for 7 secs by YFP halide assay	ec50	0.0040	uM
2-[(2-hydroxybenzoyl)amino]-5,7-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide	1471893: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o cells incubated for 10 mins in presence of forskolin measured for 7 secs by YFP halide assay	ec50	0.0040	uM
(9R)-9-(5-bromofuran-2-yl)-12,14-dimethyl-13,15-dioxo-17-phenyl-8-oxa-1,12,14-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-2(7),3,5,10,16-pentaene-4-carboxylic acid;propan-2-amine	748579: Inhibition of wild type human CFTR chloride conductance expressed in forskolin-stimulated rat FRT cells by short-circuit current analysis in presence of transepithelial chloride gradient	ic50	0.0040	uM
2,4-dimethylpyrido[1,2-a]pyrimidin-5-ium-3-olate	598317: Inhibition of wild type CFTR expressed in CHO cells by [125I]iodide efflux assay	ic50	0.0050	uM
4-[(2R,4R)-4-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid	1467971: Corrector activity at CFTR F508del/F508del mutant in primary HBE cells assessed as increase in chloride ion current across apical membrane measured 18 to 24 hrs post compound treatment on basolateral side of cells in presence of channel potentiator GLPG1837 by trans-epithelial current clamp method	ec50	0.0050	uM
3-amino-N-(3,3,3-trifluoro-2-hydroxypropyl)-5-[4-(trifluoromethoxy)piperidin-1-yl]sulfonylpyridine-2-carboxamide	1744464: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o- cells co-expressing YFP incubated for 10 mins by halide potentiator assay	ec50	0.0050	uM
(3S)-N-(4-pentylphenyl)-2-(4-propan-2-yloxypyridine-2-carbonyl)-3,4-dihydro-1H-isoquinoline-3-carboxamide	246453: Effective concentration for cellular chloride transport in C127 mouse epithelial cell transfected with recombinant Delta F508 CFTR	ec50	0.0060	uM
7-(3,4-dimethoxyphenyl)-N-[4-(2-morpholin-4-ylethoxy)phenyl]pyrazolo[1,5-a]pyrimidine-2-carboxamide	1965125: Activation of human wild-type CFTR stably expressed in CHO-K1 cells co-expressing halide sensors YFP-H148Q/I152L assessed as CFTR-mediated iodide influx incubated for 10 mins by YFP fluorescence quenching assay	ec50	0.0060	uM
(3S)-N-(4-pentylphenyl)-2-(3-propan-2-yloxybenzoyl)-3,4-dihydro-1H-isoquinoline-3-carboxamide	246453: Effective concentration for cellular chloride transport in C127 mouse epithelial cell transfected with recombinant Delta F508 CFTR	ec50	0.0063	uM
7-(3,4-dimethoxyphenyl)-N-(4-morpholin-4-ylphenyl)pyrazolo[1,5-a]pyrimidine-2-carboxamide	1965125: Activation of human wild-type CFTR stably expressed in CHO-K1 cells co-expressing halide sensors YFP-H148Q/I152L assessed as CFTR-mediated iodide influx incubated for 10 mins by YFP fluorescence quenching assay	ec50	0.0070	uM
3-amino-5-(4-fluorophenyl)sulfonyl-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]pyridine-2-carboxamide	1744464: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o- cells co-expressing YFP incubated for 10 mins by halide potentiator assay	ec50	0.0078	uM
3-amino-6-ethyl-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)pyridine-2-carboxamide	1814509: Potentiation of CFTR F508del mutant (unknown origin) expressed in CHO cells assessed as chloride transport by measuring membrane potential incubated for 5 to 30 mins in presence of forskolin by Quattro assay	ec50	0.0080	uM
9-(5-bromofuran-2-yl)-12,14-dimethyl-13,15-dioxo-17-phenyl-8-oxa-1,12,14-triazatetracyclo[8.7.0.02,7.011,16]heptadeca-2(7),3,5,10,16-pentaene-4-carboxylic acid	619074: Inhibition of human wild-type CFTR expressed in FRT cells assessed as inhibition of forskolin-induced short-circuit current by voltage clamp electrophysiology assay	ic50	0.0080	uM
4-[(2R,4R)-4-[[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonyl]amino]-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid	1467971: Corrector activity at CFTR F508del/F508del mutant in primary HBE cells assessed as increase in chloride ion current across apical membrane measured 18 to 24 hrs post compound treatment on basolateral side of cells in presence of channel potentiator GLPG1837 by trans-epithelial current clamp method	ec50	0.0090	uM
1-benzyl-3-(3-nitrophenyl)quinoxalin-2-one	1441987: Activation of human CFTR expressed in FRT cells co-expressing YFP H148Q mutant assessed as increase in forskolin-stimulated iodide influx measured after 10 mins by fluorescence assay	ec50	0.0090	uM
3-amino-N-[(2S)-3,3,3-trifluoro-2-hydroxy-2-methylpropyl]-5,6-bis(trifluoromethyl)pyridine-2-carboxamide	1814509: Potentiation of CFTR F508del mutant (unknown origin) expressed in CHO cells assessed as chloride transport by measuring membrane potential incubated for 5 to 30 mins in presence of forskolin by Quattro assay	ec50	0.0090	uM
3-amino-6-bromo-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-5-(trifluoromethyl)pyridine-2-carboxamide	1814509: Potentiation of CFTR F508del mutant (unknown origin) expressed in CHO cells assessed as chloride transport by measuring membrane potential incubated for 5 to 30 mins in presence of forskolin by Quattro assay	ec50	0.0090	uM
N-(3-tert-butyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide	1172572: Potentiation of human CFTR F508del mutant expressed in mouse NIH-3T3 cells after 30 mins by fluorescent voltage sensing optical assay	ec50	0.0090	uM
(3S)-2-(4-cyclohexyloxypyridine-2-carbonyl)-N-(4-pentylphenyl)-3,4-dihydro-1H-isoquinoline-3-carboxamide	246453: Effective concentration for cellular chloride transport in C127 mouse epithelial cell transfected with recombinant Delta F508 CFTR	ec50	0.0094	uM
3-(3-nitrophenyl)-1-(thiophen-2-ylmethyl)quinoxalin-2-one	1441987: Activation of human CFTR expressed in FRT cells co-expressing YFP H148Q mutant assessed as increase in forskolin-stimulated iodide influx measured after 10 mins by fluorescence assay	ec50	0.0100	uM
(3S)-2-[3-(2-methylpropoxy)benzoyl]-N-(4-pentylphenyl)-3,4-dihydro-1H-isoquinoline-3-carboxamide	246453: Effective concentration for cellular chloride transport in C127 mouse epithelial cell transfected with recombinant Delta F508 CFTR	ec50	0.0100	uM
3-amino-6-bromo-N-[3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propyl]-5-(trifluoromethyl)pyridine-2-carboxamide	1814509: Potentiation of CFTR F508del mutant (unknown origin) expressed in CHO cells assessed as chloride transport by measuring membrane potential incubated for 5 to 30 mins in presence of forskolin by Quattro assay	ec50	0.0100	uM
(3S)-N-(4-pentylphenyl)-2-(2-propan-2-yloxypyridine-4-carbonyl)-3,4-dihydro-1H-isoquinoline-3-carboxamide	246453: Effective concentration for cellular chloride transport in C127 mouse epithelial cell transfected with recombinant Delta F508 CFTR	ec50	0.0110	uM
N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-5-methyl-1H-pyrazole-3-carboxamide	1471893: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o cells incubated for 10 mins in presence of forskolin measured for 7 secs by YFP halide assay	ec50	0.0110	uM
3-amino-N-[(2S)-2-hydroxypropyl]-5-[4-(trifluoromethoxy)phenyl]sulfonylpyridine-2-carboxamide	1744464: Potentiation of CFTR F508del mutant (unknown origin) expressed in human CFBE41o- cells co-expressing YFP incubated for 10 mins by halide potentiator assay	ec50	0.0110	uM
N-(5-tert-butyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide	1172572: Potentiation of human CFTR F508del mutant expressed in mouse NIH-3T3 cells after 30 mins by fluorescent voltage sensing optical assay	ec50	0.0110	uM
(3S)-2-(4-methoxy-3-phenoxybenzoyl)-N-(4-pentylphenyl)-3,4-dihydro-1H-isoquinoline-3-carboxamide	246453: Effective concentration for cellular chloride transport in C127 mouse epithelial cell transfected with recombinant Delta F508 CFTR	ec50	0.0120	uM

CTD chemical–gene interactions

170 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Chlorides	increases reaction, increases export, increases secretion, decreases transport, decreases secretion (+7 more)	15
Colforsin	affects cotreatment, increases transport, increases reaction, affects localization, affects export (+5 more)	15
Glyburide	affects binding, decreases activity, decreases reaction, increases activity, affects cotreatment (+1 more)	10
fenamic acid	affects cotreatment, decreases reaction, increases activity, increases transport, decreases activity	7
3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone	increases reaction, affects cotreatment, increases activity, increases transport, decreases activity (+2 more)	7
5-nitro-2-(3-phenylpropylamino)benzoic acid	affects binding, increases activity, decreases activity	5
N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide	decreases activity, affects localization, decreases reaction, increases activity, increases phosphorylation	5
ivacaftor	affects cotreatment, increases activity, decreases activity, decreases reaction, affects transport (+1 more)	5
Tobacco Smoke Pollution	affects expression, decreases activity, decreases expression	5
Valproic Acid	affects cotreatment, increases expression	5
Genistein	affects localization, affects export, affects cotreatment, decreases reaction, increases activity (+2 more)	5
5-butyl-6-hydroxy-10-chlorobenzo(c)quinolizinium chloride	affects cotreatment, increases activity, decreases reaction, increases transport, increases stability (+1 more)	4
Resveratrol	affects cotreatment, decreases expression, increases activity	4
Adenosine Triphosphate	affects binding, affects cotreatment, decreases reaction, increases export, increases reaction (+2 more)	4
1-Methyl-3-isobutylxanthine	affects export, increases reaction, affects cotreatment, increases activity	4
4-phenylbutyric acid	increases activity, increases stability, affects localization	3
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	increases activity, decreases expression, affects localization, decreases reaction, increases expression	3
U 0126	decreases expression, decreases activity, decreases reaction, increases activity	3
5-butyl-7-chloro-6-hydroxybenzo(c)quinolizinium	affects cotreatment, decreases reaction, increases transport, increases activity, increases expression (+2 more)	3
Cyclic AMP	increases activity, increases reaction, increases transport	3
Ascorbic Acid	increases activity, affects cotreatment, decreases activity, decreases reaction, increases reaction (+1 more)	3
Bicarbonates	affects cotreatment, increases activity, decreases activity, decreases transport, increases transport (+1 more)	3
Curcumin	decreases reaction, increases export, increases phosphorylation, increases reaction, affects reaction (+1 more)	3
Gentamicins	increases activity, increases expression	3
Glutathione	decreases activity, decreases reaction, affects cotreatment, increases activity	3
sodium arsenite	decreases expression, decreases reaction, increases secretion, increases expression, decreases activity	2
mercuric bromide	increases expression, affects cotreatment	2
7,8-benzoquinoline	increases activity, affects secretion, increases reaction	2
6-hydroxy-10-chlorobenzo(c)quinolizinium	decreases reaction, increases transport, increases activity, affects cotreatment	2
4-chlorobenzo(f)isoquinoline	increases activity	2

ChEMBL screening assays

520 unique, capped per target: 497 binding, 17 functional, 5 admet, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1737974	Binding	PUBCHEM_BIOASSAY: Fluorescence Polarization with Cer CAL-PDZ Measured in Biochemical System Using Plate Reader - 2109-01_Inhibitor_Dose_CherryPick_Activity. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID50443	PubChem BioAssay data set
CHEMBL1963993	Functional	PUBCHEM_BIOASSAY: Fluorescence Polarization with Cer CAL-PDZ Measured in Biochemical System Using Plate Reader - 2109-01_Inhibitor_Dose_DryPowder_Activity. (Class of assay: confirmatory)	PubChem BioAssay data set
CHEMBL4310428	ADMET	Inhibition of wild type human CFTR expressed in FRT cells assessed as reduction in forskolin-induced chloride current at 30 to 100 uM after 20 mins by electrophysiological assay	Synthesis and biological evaluation of novel Ani9 derivatives as potent and selective ANO1 inhibitors. — Eur J Med Chem

Cellosaurus cell lines

283 cell lines: 157 transformed cell line, 54 induced pluripotent stem cell, 44 finite cell line, 21 embryonic stem cell, 4 cancer cell line, 3 telomerase immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_0338	IB3-1	Transformed cell line	Male
CVCL_0486	PLJ-4.7	Cancer cell line	Male
CVCL_0M12	GM01957	Finite cell line	Male
CVCL_0M13	GM01958	Finite cell line	Male
CVCL_0M14	GM01959	Finite cell line	Male
CVCL_0M15	GM02801	Finite cell line	Male
CVCL_0M16	GM02803	Finite cell line	Male
CVCL_0M17	GM02826	Finite cell line	Female
CVCL_0M18	GM02827	Finite cell line	Female
CVCL_0M19	GM02828	Finite cell line	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00157690	PHASE4	COMPLETED	Study of Alendronate to Prevent and Treat Osteoporosis in Cystic Fibrosis Patients
NCT00208078	PHASE4	TERMINATED	Effect of Non-Invasive Ventilation in Cystic Fibrosis Patient With Chronic Respiratory Failure.
NCT00244270	PHASE4	COMPLETED	Cystic Fibrosis and Totally Implantable Vascular Access Devices
NCT00333385	PHASE4	TERMINATED	Continuous Versus Short Infusions of Ceftazidime in Cystic Fibrosis
NCT00411736	PHASE4	COMPLETED	Scandinavian Cystic Fibrosis Azithromycin Study
NCT00418470	PHASE4	TERMINATED	Prolonging the Duration of Peripheral Venous Catheters in Cystic Fibrosis People
NCT00431964	PHASE4	COMPLETED	Effect of Azithromycin on Lung Function in 6-18 Year-olds With Cystic Fibrosis (CF) Not Infected With P. Aeruginosa
NCT00434278	PHASE4	TERMINATED	A Trial of Pulmozyme Withdrawal on Exercise Tolerance in Cystic Fibrosis Subjects With Severe Lung Disease (TOPIC)
NCT00483769	PHASE4	COMPLETED	One Year Glargine Treatment in CFRD Children and Adolescents
NCT00528190	PHASE4	COMPLETED	Treatment of Aspergillus Fumigatus (a Fungal Infection) in Patients With Cystic Fibrosis
NCT00557089	PHASE4	COMPLETED	The Effect of rhDNase on Ventilation Inhomogeneity in Patients With Cystic Fibrosis
NCT00572975	PHASE4	COMPLETED	Malabsorption Blood Test:Toward a Novel Approach to Quantify Steatorrhea
NCT00680316	PHASE4	TERMINATED	A Study of Pulmozyme® (Dornase Alpha) in 3- to 5-Year-Old Patients With Cystic Fibrosis
NCT00685035	PHASE4	COMPLETED	Comparison of Airway Clearance Therapy in Cystic Fibrosis Using the Same VEST Therapy Device But With Different Settings
NCT00744250	PHASE4	TERMINATED	Intraduodenal Aspiration Study to Assess the Bioavailability of Oral Pancrecarb® Compared to Placebo Control
NCT00787917	PHASE4	TERMINATED	An Exploratory Study to Assess Multiple Doses of Omalizumab in Patients With Cystic Fibrosis Complicated by Acute Bronchopulmonary Aspergillosis (ABPA)
NCT00843817	PHASE4	COMPLETED	RhDNase and Biodistribution of PMN Serine Proteases in Cystic Fibrosis Sputum
NCT00890370	PHASE4	COMPLETED	Should Any One Airway Clearance Technique be Recommended for People With Cystic Fibrosis?
NCT00996424	PHASE4	TERMINATED	The Effect of Inhaled N-Acetylcysteine Compared to Normal Saline on Sputum Rheology and Lung Function
NCT01044719	PHASE4	UNKNOWN	Duration of Antibiotics in Infective Exacerbations of Cystic Fibrosis
NCT01100606	PHASE4	COMPLETED	A Study to Evaluate the Mode of Administration and Safety of EUR-1008 (APT-1008) in Infants 1 to 12 Months of Age
NCT01131507	PHASE4	COMPLETED	PR-018: An Open-Label, Safety Extension of Study PR-011
NCT01207245	PHASE4	COMPLETED	Circadian Rhythm In Tobramycin Elimination In Cystic Fibrosis
NCT01323101	PHASE4	COMPLETED	Doxycycline Effects on Inflammation in Cystic Fibrosis
NCT01327703	PHASE4	COMPLETED	Control of Steatorrhea in Participants With Cystic Fibrosis and Exocrine Pancreatic Insufficiency
NCT01377792	PHASE4	COMPLETED	Study of Long-term Treatment With Hypertonic Saline in Patients With Cystic Fibrosis
NCT01400750	PHASE4	COMPLETED	Comparison of 2 Treatment Regimens for Eradication of P Aeruginosa Infection in Children With Cystic Fibrosis
NCT01429259	PHASE4	COMPLETED	Population Pharmacokinetics of Prolonged Infusion Meropenem in Cystic Fibrosis (CF) Children
NCT01608555	PHASE4	COMPLETED	Tobramycin 300 mg Once-a-day (o.d.) Aerosol in Adults With Cystic Fibrosis
NCT01667094	PHASE4	UNKNOWN	A Study Comparing Continuous Infusion Antibiotics to Standard Treatment for Lung Infections in Cystic Fibrosis
NCT01694069	PHASE4	TERMINATED	Continuous Infusion Piperacillin-tazobactam for the Treatment of Cystic Fibrosis
NCT01702415	PHASE4	WITHDRAWN	Zoledronic Acid in Cystic Fibrosis
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